Article

Preeclampsia is associated with reduced serum levels of placenta growth factor

January 1999
American Journal of Obstetrics and Gynecology 179(6 Pt 1):1539-44

January 1999
179(6 Pt 1):1539-44

DOI:10.1016/S0002-9378(98)70021-3

Source
PubMed

Authors:

Hansheng Wang

Chinese Academy of Sciences

Show all 5 authorsHide

Adequate vascular development of the placental bed is essential for normal pregnancy. We assessed serum levels of placenta growth factor, an angiogenic factor, throughout normal pregnancy and determined its association with preeclampsia. Serum samples were collected from (1) 308 healthy pregnant women throughout normal gestation, (2) at delivery from 30 each gestational age-matched patients with normal pregnancy and preeclampsia, and (3) maternal and cord blood samples from normal deliveries with and without labor (n = 37 each). Placenta growth factor levels were determined with an antigen-capture enzyme-linked immunosorbent assay. Maternal placenta growth factor levels during normal pregnancy increased from the first trimester to the late second trimester; they subsequently declined from 30 weeks' gestation to delivery. Significantly less maternal placenta growth factor (P <.0001) was found in pregnancies complicated by preeclampsia, and labor significantly lowered placenta growth factor levels in both maternal (P =.0189) and cord serum samples (P <.0001). Decreased levels of placenta growth factor during preeclampsia could influence endothelial cell and trophoblast function, thereby contributing to the pathogenesis of the disease.

Preeclampsia may influence offspring neuroanatomy and cognitive function: A role for placental growth factor?

Article

Full-text available

Jun 2019
BIOL REPROD

Preeclampsia (PE) is a common pregnancy complication affecting 3-5% of women. PE is diagnosed clinically as new-onset hypertension with associated end organ damage after 20 weeks of gestation. Despite being diagnosed as a maternal syndrome, fetal experience of PE is a developmental insult with lifelong cognitive consequences. These cognitive alterations are associated with distorted neuroanatomy and cerebrovasculature, including a higher risk of stroke. The pathophysiology of a PE pregnancy is complex, with many factors potentially able to affect fetal development. Deficient pro-angiogenic factor expression is one aspect that may impair fetal vascularization, alter brain structure and affect future cognition. Of the pro-angiogenic growth factors, placental growth factor (PGF) is strongly linked to PE. Concentrations of PGF are inappropriately low in maternal blood both before and during a PE gestation. Fetal concentrations of PGF appear to mirror maternal circulating concentrations. Using Pgf-/- mice that may model effects of PE on offspring, we demonstrated altered central nervous system vascularization, neuroanatomy and behaviour. Overall, we propose that development of the fetal brain is impaired in PE, making the offspring of preeclamptic pregnancies a unique cohort with greater risk of altered cognition and cerebrovasculature. These individuals may benefit from early interventions, either pharmacological or environmental. The early neonatal period may be a promising window for intervention while the developing brain retains plasticity.

Effects of placental growth factor deficiency on behavior, neuroanatomy and cerebrovasculature of mice

Article

Full-text available

Aug 2018

Preeclampsia, a hypertensive syndrome occurring in 3-5% of human pregnancies, has lifelong health consequences for the fetus. Cognitive ability throughout life is altered and adult stroke risk is increased in these offspring. One potential etiological factor for altered brain development is low concentrations of pro-angiogenic placental growth factor (PGF). Impaired PGF production may promote an anti-angiogenic fetal environment during neural and cerebrovascular development. We previously reported delayed vascularization of the hindbrain, altered retinal vascular organization and less connectivity in the circle of Willis in Pgf-/- mice. We hypothesized Pgf-/- mice would have impaired cognition and altered brain neuroanatomy in addition to compromised cerebrovasculature. Cognitive behavior was assessed in adult Pgf-/- and Pgf+/+ mice by four paradigms followed by post-mortem high-resolution MRI of neuroanatomy. X-ray micro-computed tomography imaging investigated the 3D cerebrovascular geometry. Pgf-/- mice exhibited poorer spatial memory, less depressive-like behavior and superior recognition of novel objects. Significantly smaller volumes of 10 structures were detected in the Pgf-/- compared to Pgf+/+ brain. Pgf-/- brain had more total blood vessel segments in the small-diameter range. Lack of PGF altered cognitive functions, brain neuroanatomy and cerebrovasculature in mice. Pgf-/- mice may be a preclinical model for the offspring effects of low-PGF PE gestation.

Serum Levels of Angiogenic Factors Distinguish Between Women with Preeclampsia and Normotensive Pregnant Women But Not Severity of Preeclampsia in an Obstetric Center in Turkey

Article

Full-text available

Sep 2019
MED SCI MONITOR

Tolga Atakul

Background This study aimed to compare serum levels of vascular endothelial growth factor (VEGF) and the VEGF receptors, VEGFR-1 and VEGFR-2, free placental growth factor (fPGF), endostatin, and serum pregnancy-associated plasma protein-A (PAPP-A) levels in women with mild and severe preeclampsia and healthy pregnant women. Material/Methods A included patients diagnosed with mild preeclampsia (n=32), severe preeclampsia (n=32), and healthy pregnant women (n=24). Serum levels of VEGF-A, VEGFR-1, VEGFR-2, fPGF, endostatin, and PAPP-A levels were measured by enzyme-linked immunosorbent assay (ELISA). Results In women with mild and severe preeclampsia, the gestation age at birth and birth weight were found to be significantly lower than the control group (p<0.001). Serum levels of endostatin, VEGFR-1, and VEGF-A levels were significantly increased in pregnant women with preeclampsia compared with healthy pregnant women (p<0.001). Serum levels of PAPP-A, VEGFR-2, and fPGF were significantly higher in healthy pregnant women when compared with women with preeclampsia (p=0.024, p<0.001, and p<0.001, respectively), but there were no significant differences between women with mild and severe preeclampsia. Conclusions Reduced serum levels of the angiogenic factors PAPP-A, VEGFR-2, and fPGF distinguished between women with preeclampsia and normotensive pregnant women but did not significantly distinguish between mild and severe preeclampsia.

Vascular Endothelial Growth Factor Delivery to Placental Basal Plate Promotes Uterine Artery Remodeling in the Primate

Article

Apr 2019
ENDOCRINOLOGY

Extravillous trophoblast (EVT) uterine artery remodeling (UAR) promotes placental blood flow, but UAR regulation is unproven. Elevating estradiol (E2) in early baboon pregnancy suppressed UAR and EVT vascular endothelial growth factor (VEGF) expression, but this did not prove VEGF mediated this process. Therefore, our primate model of prematurely elevating E2 and contrast-enhanced ultrasound cavitation of microbubble carriers (CEU/MB) were used to deliver VEGF DNA to the placental basal plate (PBP) to establish VEGF role in UAR. Baboons treated on days 25-59 of gestation (term = 184 days) with E2 alone or with E2 plus VEGF DNA conjugated MB briefly infused via a maternal peripheral vein on days 25, 35, 45 and 55. At each of these times an ultrasound beam was directed to the PBP to collapse the MB and release VEGF DNA. VEGF DNA labeled MB/contrast agent was localized in the PBP but not the fetus. Remodeling of uterine arteries >25 µm in diameter on day 60 was 75% lower (P<0.001) in E2-treated (7 ± 2%) than in untreated baboons (30 ± 4%) and restored to normal by E2/VEGF. VEGF protein levels (signals/nuclear area) within the PBP were 2-fold lower (P<0.01) in E2-treated (4.2 ± 0.9) than in untreated (9.8 ± 2.8) baboons and restored to normal by E2/ VEGF (11.9 ± 1.6), substantiating VEGF transfection. Thus, VEGF gene delivery selectively to the PBP prevented the decrease in UAR elicited by prematurely elevating E2 levels, establishing the role of VEGF in regulating UAR in vivo during primate pregnancy.

Preeclampsia at Term Can Be Classified Into Two Clusters With Different Clinical Characteristics and Outcomes Based on Angiogenic Biomarkers in Maternal Blood

Article

Feb 2024
Obstet Anesth Digest

( Am J Obstet Gynecol. 2023;228:569.e1–569.e24) Pre-eclampsia, a complex and multisystemic disorder affecting a significant percentage of pregnancies worldwide, is a leading cause of preterm birth and maternal mortality. This condition is not uniform and can be classified into different subtypes based on gestational age and underlying pathophysiological mechanisms. Understanding these subtypes is crucial for predicting maternal and fetal outcomes and developing targeted therapeutic strategies.

HIGH SERUM RATIO OF SOLUBLE FMS-LIKE TYROSINE KINASE 1 (sFlt-1) TO PLACENTAL GROWTH FACTOR (PIGF) AND HIGH LEVEL OF LOW-DENSITY LIPOPROTEIN (LDL) AS RISK FACTORS OF PREECLAMPSIA

Article

Full-text available

Jul 2023

Preeclampsia is an obstetric disease that is a health problem worldwide, including in Indonesia. Several studies have shown that changes in the maternal spiral arteries are thought to lead to preeclampsia. Preeclampsia in this decade has been associated with changes in angiogenesis regulatory proteins originating from the placenta and circulating in the mother's blood circulation, namely soluble FMS-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF). The author was interested in examining the ratio of sFlt-1/PIGF and low-density lipoprotein (LDL) to the incidence of preeclampsia in pregnant women. This study used a case control analytic observational design. The research sample was selected by consecutive sampling of 20 cases and 20 controls. Univariate analysis was used to describe patient characteristics descriptively, and bivariate analysis was used to determine the relationship between the 2 variables There is no significant difference in the characteristics of the research subjects. Low PIGF levels are a risk factor for preeclampsia (OR 4.33; p 0.0302) with a cut-off value of 24.5. High sFlt-1 levels are a risk factor for preeclampsia (OR 4.33; p 0.027) with a cut-off value of 869.5. A high sFlt-1/PIGF ratio is a risk factor for preeclampsia (OR 4.33 p 0.030) with a cut-off value of 38. High LDL levels are a risk factor for preeclampsia (OR 6.0; p 0.013) with a cut-off value of 150 ,2. Low placental growth factor (PIGF), high levels of soluble FMS-like tyrosine kinase 1 (sFlt-1), and high levels of LDL are risk factors of preeclampsia in pregnant women.

High Serum Ratio of Soluble Fms-Like Tyrosine Kinase 1 (sFlt-1) to Placental Growth Factor (PIGF) and High Level of Low-Density Lipoprotein (LDL) as Risk Factors of Preeclampsia

Article

Full-text available

May 2023

Placental growth factor as a predictive marker of preeclampsia in twin pregnancy

Preprint

Full-text available

Jun 2023

Background: Placental growth factor (PLGF) has been reported to predict the absence of preeclampsia (PE) in singleton pregnancies. Thus, this study aims to evaluate the predictive value of the PLGF in twin pregnancies. Methods: Twin pregnancy with clinically suspected PE (24 weeks 0 days to 36 weeks 6 days of gestation) was enrolled in this study. The threshold of PLGF was determined on the basis of a receiver-operating characteristic curve to predict PE. Results: A cutoff value of 215 pg/mL for PLGF indicates a good predictive performance for PE. An area under the curve of 0.863 with 86% sensitivity and 80% specificity was also obtained. Conclusion: Effective screening for PE can be provided by the PLGF assay in twin pregnancies with clinically suspected PE.

Association of Low Placental Growth Factor Gene Expression with Maternal and Neonatal Outcomes in Type 1 Diabetes: A Single Center, Cross-Sectional Study

Article

Feb 2023

Article

Full-text available

Jan 2023
INT J MOL SCI

The purpose of this study was to evaluate serum levels of anti- and pro-angiogenic substances measured using enzyme-linked immunosorbent assays and their ratios in pregnancies complicated by different clinical subsets of placental ischemic syndrome: preeclampsia and/or fetal growth restriction. A prospective case-control study was performed consisting of 77 singleton pregnancies complicated by preeclampsia, preeclampsia with concurrent fetal growth restriction (FGR), and isolated normotensive FGR pairwise matched by gestational age with healthy pregnancies. The entire study cohort was analyzed with respect to adverse pregnancy outcomes that occurred. In all investigated subgroups, placental growth factor (PlGF) was lower and soluble endoglin (sEng), the soluble fms-like tyrosine kinase-1—sFlt-1/PlGF and sFlt-1*sEng/PlGF ratios were higher than in the control group. The differences were most strongly pronounced in the PE with concurrent FGR group and in the sFlt-1/PlGF ratio. The highest sFlt-1 values in preeclamptic patients suggest that this substance may be responsible for reaching the threshold needed for PE to develop as a maternal manifestation of ischemic placental disease. The FGR is characterized by an elevated maternal sFlt-1/PlGF ratio, which boosts at the moment of indicated delivery due to fetal risk. We concluded that angiogenic imbalance is reflective of placental disease regardless of its clinical manifestation in the mother, and may be used as support for the diagnosis and prognosis of FGR.

Role of hydrogen sulphide in physiological and pathological angiogenesis

Article

Full-text available

Dec 2022
CELL PROLIFERAT

The role of hydrogen sulphide (H2S) in angiogenesis has been widely demonstrated. Vascular endothelial growth factor (VEGF) plays an important role in H2S‐induced angiogenesis. H2S promotes angiogenesis by upregulating VEGF via pro‐angiogenic signal transduction. The involved signalling pathways include the mitogen‐activated protein kinase pathway, phosphoinositide‐3 kinase pathway, nitric oxide (NO) synthase/NO pathway, signal transducer and activator of transcription 3 (STAT3) pathway, and adenosine triphosphate (ATP)‐sensitive potassium (KATP) channels. H2S has been shown to contribute to tumour angiogenesis, diabetic wound healing, angiogenesis in cardiac and cerebral ischaemic tissues, and physiological angiogenesis during the menstrual cycle and pregnancy. Furthermore, H2S can exert an anti‐angiogenic effect by inactivating Wnt/β‐catenin signalling or blocking the STAT3 pathway in tumours. Therefore, H2S plays a double‐edged sword role in the process of angiogenesis. The regulation of H2S production is a promising therapeutic approach for angiogenesis‐associated diseases. Novel H2S donors and/or inhibitors can be developed in the treatment of angiogenesis‐dependent diseases. Hydrogen sulphide and nitric oxide interact and depend on each other to jointly regulate angiogenesis.

Toward a new taxonomy of obstetrical disease: improved performance of maternal blood biomarkers for the great obstetrical syndromes when classified according to placental pathology

Article

Full-text available

Sep 2022
AM J OBSTET GYNECOL

Background The major challenge for obstetrics is the prediction and prevention of the great obstetrical syndromes. We propose that defining obstetrical diseases by the combination of clinical presentation and disease mechanisms as inferred by placental pathology will aid in the discovery of biomarkers and add specificity to those already known. Objective To describe the longitudinal profile of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PlGF/sFlt-1 ratio throughout gestation, and to determine whether the association between abnormal biomarker profiles and obstetrical syndromes is strengthened by information derived from placental examination, eg, the presence or absence of placental lesions of maternal vascular malperfusion. Study Design This retrospective case cohort study was based on a parent cohort of 4006 pregnant women enrolled prospectively. The case cohort of 1499 pregnant women included 1000 randomly selected patients from the parent cohort and all additional patients with obstetrical syndromes from the parent cohort. Pregnant women were classified into six groups: 1) term delivery without pregnancy complications (n=540; control); 2) preterm labor and delivery (n=203); 3) preterm premature rupture of the membranes (n=112); 4) preeclampsia (n=230); 5) small-for-gestational-age neonate (n=334); and 6) other pregnancy complications (n=182). Maternal plasma concentrations of PlGF and sFlt-1 were determined by enzyme-linked immunosorbent assays in 7560 longitudinal samples. Placental pathologists, masked to clinical outcomes, diagnosed the presence or absence of placental lesions of maternal vascular malperfusion. Comparisons between mean biomarker concentrations in cases and controls were performed by utilizing longitudinal generalized additive models. Comparisons were made between controls and each obstetrical syndrome with and without subclassifying cases according to the presence or absence of placental lesions of maternal vascular malperfusion. Results 1) When obstetrical syndromes are classified based on the presence or absence of placental lesions of maternal vascular malperfusion, significant differences in the mean plasma concentrations of PlGF, sFlt-1, and the PlGF/sFlt-1 ratio between cases and controls emerge earlier in gestation; 2) the strength of association between an abnormal PlGF/sFlt-1 ratio and the occurrence of obstetrical syndromes increases when placental lesions of maternal vascular malperfusion are present (adjusted odds ratio [aOR], 13.6 vs 6.7 for preeclampsia; aOR, 8.1 vs 4.4 for small-for-gestational-age neonates; aOR, 5.5 vs 2.1 for preterm premature rupture of the membranes; and aOR, 3.3 vs 2.1 for preterm labor (all P<0.05); and 3) the PlGF/sFlt-1 ratio at 28 to 32 weeks of gestation is abnormal in patients who subsequently delivered due to preterm labor with intact membranes and in those with preterm premature rupture of the membranes if both groups have placental lesions of maternal vascular malperfusion. Such association is not significant in patients with these obstetrical syndromes who do not have placental lesions. Conclusion Classification of obstetrical syndromes according to the presence or absence of placental lesions of maternal vascular malperfusion allows biomarkers to be informative earlier in gestation and enhances the strength of association between biomarkers and clinical outcomes. We propose that a new taxonomy of obstetrical disorders informed by placental pathology will facilitate the discovery and implementation of biomarkers as well as the prediction and prevention of such disorders.

Long-term observational study of renal outcome after preeclampsia: Role of soluble fms-like tyrosine kinase-1(sFlt-1)/ placental growth factor (PlGF) and endoglin

Article

Full-text available

May 2022

Introduction Preeclampsia (PE) is an important complication of pregnancy that can lead to chronic kidney disease. Soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), the sFlt-1/PlGF ratio and endoglin are biomarkers for the differential diagnosis of PE and other diseases. We aimed to explore the correlation of these biomarkers with long-term renal function, blood pressure and the urine albumin/creatinine ratio (UACR) in PE patients. Methods 34 patients with PE were enrolled. Blood samples for sFlt-1, PlGF, endoglin and the urine albumin/creatinine ratio (UACR) were collected at the time of PE diagnosis (at 35–40 weeks’ gestational age (GA) (87.50% of cases). After delivery, the patients were followed up at three months and one year to assess blood pressure, renal function and the UACR. Results Thirty-four PE patients were included, and 17 completed the study. The estimated glomerular filtration rate (eGFR) decreased significantly at three months and one year after follow-up (128.20 ± 10.34 to 120.75 ± 10.166 ml/min/1.73 m² (p = 0.001) at three months and 126.71 ± 9.948 to 114.29 ± 11.274 ml/min/1.73 m² (p < 0.001) at one year). The endoglin level correlated significantly with the eGFR level during PE, but there was no correlation of any biomarker with eGFR, blood pressure, or the UACR at one year. Conclusion Women with PE have a reduction of eGFR at three months and one year after the diagnosis of PE. Only endoglin is correlated with eGFR antepartum; however, it is not correlated with long-term renal function, blood pressure or the UACR.

EL ORIGEN DE LA PREECLAMPSIA Y LA ECLAMPSIA: LA PLACENTACIÓN

Article

Apr 2015

Percy Pacora Portella

La entidad constituida por preeclampsia y eclampsia es la principal causa de morbilidad y mortalidad de la madre y el niño en el Perú. La preeclampsia y eclampsia consiste en un síndrome materno y fetal, secundario a la placentación defectuosa y exceso en la producción placentaria de sFlt-1, una molécula antiangiogénica denominada forma soluble de la tirosinaquinasa- 1 similar al fms (sFlt-1, también llamado sVEGFR-1). La sFlt-1 actúa antagonizando dos moléculas angiogénicas –factor de crecimiento endotelial vascular (VEGF) y factor de crecimiento placentario (PLGF). El desbalance angiogénico es importante para la diferenciación e invasión de los citotrofoblastos. La placentación anormal y la hipoxia subsiguiente pueden, a su vez, ocasionar mayor producción de sFlt-1, conduciendo a un círculo vicioso de mayor producción de sFlt-1, eventualmente causando la preeclampsia. La preeclampsia y la eclampsia son manifestación de la enfermedad vascular del embarazo y ocurre por la participación de factores genéticos y ambientales: anatómico, hereditario, nutricional, inflamatorio (infeccioso), contaminación fisicoquímica, metabólico, emocional y social. Las manifestaciones clínicas del síndrome son manifestaciones del daño endotelial en el compartimiento materno y/o fetal. Las convulsiones eclámpticas pueden ocurrir en ausencia de hipertensión arterial y proteinuria. El estudio de la placenta es obligatorio, para establecer el diagnóstico de enfermedad vascular del embarazo. Y es necesario conocer el estado de salud de la madre y el niño luego del nacimiento, para establecer la gravedad del síndrome clínico.

Syncytiotrophoblast stress in preeclampsia: the convergence point for multiple pathways

Article

Feb 2021
AM J OBSTET GYNECOL

Preeclampsia evolves in 2 stages: a placental problem that generates signals to the mother to cause a range of responses that comprise the second stage (preeclampsia syndrome). The first stage of early-onset preeclampsia is poor placentation, which we here call malplacentation. The spiral arteries are incompletely remodeled, leading to later placental malperfusion, relatively early in the second half of pregnancy. The long duration of the first stage (several months) is unsurprisingly associated with fetal growth restriction. The first stage of late-onset preeclampsia, approximately 80% of total cases, is shorter (several weeks) and part of a process that is common to all pregnancies. Placental function declines as it outgrows uterine capacity, with increasing chorionic villous packing, compression of the intervillous space, and fetal hypoxia, and causes late-onset clinical presentations such as “unexplained” stillbirths, late-onset fetal growth restriction, or preeclampsia. The second stages of early- and late-onset preeclampsia share syncytiotrophoblast stress as the most relevant feature that causes the maternal syndrome. Syncytiotrophoblast stress signals in the maternal circulation are probably the most specific biomarkers for preeclampsia. In addition, soluble fms-like tyrosine kinase-1 (mainly produced by syncytiotrophoblast) is the best-known biomarker and is routinely used in clinical practice in many locations. How the stress signals change over time in normal pregnancies indicates that syncytiotrophoblast stress begins on average at 30 to 32 weeks’ gestation and progresses to term. At term, syncytiotrophoblast shows increasing markers of stress, including apoptosis, pyroptosis, autophagy, syncytial knots, and necrosis. We label this phenotype the “twilight placenta” and argue that it accounts for the clinical problems of postmature pregnancies. Senescence as a stress response differs in multinuclear syncytiotrophoblast from that of mononuclear cells. Syncytiotrophoblast irreversibly acquires part of the senescence phenotype (cell cycle arrest) when it is formed by cell fusion. The 2 pathways converge on the common pathologic endpoint, syncytiotrophoblast stress, and contribute to preeclampsia subtypes. We highlight that the well-known heterogeneity of the preeclampsia syndrome arises from different pathways to this common endpoint, influenced by maternal genetics, epigenetics, lifestyle, and environmental factors with different fetal and maternal responses to the ensuing insults. This complexity mandates a reassessment of our approach to predicting and preventing preeclampsia, and we summarize research priorities to maximize what we can learn about these important issues.

PREEKLAMPSIYE BAĞLI PLASENTAL DEĞİŞİKLİKLERİN İMMUNOHİSTOKİMYASAL İNCELENMESİ

Article

Full-text available

Dec 2020

Preeclampsia: Pathophysiology and management

Article

Nov 2020

Preeclampsia is a pregnancy-related multisystem disorder, frequently encountered pregnancy-related medical complications next to gestational diabetes mellitus. It is the onset of hypertension during pregnancy. The preeclampsia can be of two types, placental or maternal preeclampsia. Among these two types former, i.e., placental preeclampsia is more severe than the latter. According to the recent survey by National Health Portal of India, the incidence of preeclampsia is about 8–10 % among pregnant women. Though our understanding of preeclampsia has improved in recent years, the development and interpretation of the clinical tests remain difficult for preeclampsia. Hence, we have made an attempt to understand the pathophysiology, associated conditions/consequences, treatment and management/ prevention of the condition in this review.

Regulation of Uterine Spiral Artery Remodeling: a Review

Article

Full-text available

Jun 2020

Extravillous trophoblast remodeling of the uterine spiral arteries is essential for promoting blood flow to the placenta and fetal development, but little is known about the regulation of this process. A defect in spiral artery remodeling underpins adverse conditions of human pregnancy, notably early-onset preeclampsia and fetal growth restriction, which result in maternal and fetal morbidity and mortality. Many in vitro studies have been conducted to determine the ability of growth and other factors to stimulate trophoblast cells to migrate across a synthetic membrane. Clinical studies have investigated whether the maternal levels of various factors are altered during abnormal human pregnancy. Animal models have been established to assess the ability of various factors to recapitulate the pathophysiological symptoms of preeclampsia. This review analyzes the results of the in vitro, clinical, and animal studies and describes a nonhuman primate experimental paradigm of defective uterine artery remodeling to study the regulation of vessel remodeling.

Consensus statement on the potential implementation of the sFlt-1/PlGF ratio in women with suspected pre-eclampsia

Article

Full-text available

Dec 2018
SAJOG-S AFR J OBSTET

Pre-eclampsia is one of the leading causes of maternal and perinatal mortality and morbidity worldwide, and places a significant burden on the South African (SA) healthcare system. The soluble fms-like tyrosince kinase (sFlt-1)/placental growth factor (PlGF) ratio can serve as a diagnostic aid for PE, and should be used in combination with clinical judgement and other ancillary tests. The Preeclampsia Advisory Board was convened on 31 March 2017, with experts in the field of PE from various hospitals and universities around the country in attendance. An international expert gave insight into best practices from countries that have implemented the Elecsys immunoassay sFlt-1/PlGF ratio. Others recommend that the sFlt-1/PlGF ratio be implemented in clinical practice when clinical diagnosis is in doubt in patients with suspected PE, in the interests of avoiding unnecessary hospitalisation and interventions. The strength of the test lies in its negative predictive value in ruling out PE. Ruling out PE could drive cost savings, as fewer women would be needlessly admitted to hospital, and there could, in addition, be fewer iatrogenic preterm deliveries, which are associated with considerable morbidity and cost. As most data are derived from high-income countries, multicentre studies are required to assess the clinical performance of this test within the context of SA. © 2018, South African Medical Association. All rights reserved.

Consensus statement on the potential implementation of the sFlt-1/PlGF ratio in women with suspected pre-eclampsia

Article

Full-text available

Dec 2018

RESEARCH Pre-eclampsia is one of the leading causes of maternal and perinatal mortality and morbidity worldwide, and places a significant burden on the South African (SA) healthcare system. The soluble fms-like tyrosince kinase (sFlt-1)/placental growth factor (PlGF) ratio can serve as a diagnostic aid for PE, and should be used in combination with clinical judgement and other ancillary tests. The Preeclampsia Advisory Board was convened on 31 March 2017, with experts in the field of PE from various hospitals and universities around the country in attendance. An international expert gave insight into best practices from countries that have implemented the Elecsys immunoassay sFlt-1/PlGF ratio. Others recommend that the sFlt-1/PlGF ratio be implemented in clinical practice when clinical diagnosis is in doubt in patients with suspected PE, in the interests of avoiding unnecessary hospitalisation and interventions. The strength of the test lies in its negative predictive value in ruling out PE. Ruling out PE could drive cost savings, as fewer women would be needlessly admitted to hospital, and there could, in addition, be fewer iatrogenic preterm deliveries, which are associated with considerable morbidity and cost. As most data are derived from high-income countries, multicentre studies are required to assess the clinical performance of this test within the context of SA.

5.55 Maternal Prenatal Depression and Risk for Children's Poor Socioemotional Development: A Meta-Analysis

Article

Oct 2018
J AM ACAD CHILD PSY

Changes in pregnancy-related serum biomarkers early in gestation are associated with later development of preeclampsia

Preprint

Full-text available

Sep 2018

Background: Placental protein expression plays a crucial biological role during normal and complicated pregnancies. We hypothesized that: (1) circulating pregnancy-associated, placenta-related protein levels throughout gestation reflect the uncomplicated, full-term temporal progression of human gestation, and effectively estimates gestational ages (GAs); (2) pregnancies with underlying placental pathology, such as preeclampsia (PE), are associated with disruptions in this GA estimation in early gestation; (3) malfunctions of this GA estimation can be employed to identify impending PE. In addition, to explore the underlying biology and PE etiology, we set to compare protein gestational patterns of human and mouse, using pregnant heme oxygenase-1 (HO-1) heterozygote (Het) mice, a mouse model reflecting PE-like symptoms. Methods: Serum levels of circulating placenta-related proteins-leptin (LEP), chorionic somatomammotropin hormone like 1 (CSHL1), elabela (ELA), activin A, soluble fms-like tyrosine kinase 1 (sFlt-1), and placental growth factor (PlGF)-were quantified by ELISA in blood serially collected throughout human pregnancies (20 normal subjects with 66 samples, and 20 PE subjects with 61 samples). Linear multivariate analysis of the targeted serological protein levels was performed to estimate the normal GA. Logarithmic transformed mean-squared errors of GA estimations were used to identify impending PE. Then the human gestational protein patterns were compared to those in the pregnant HO-1 mice. Results: An elastic net (EN)-based gestational dating model was developed (R2 = 0.76) and validated (R2 = 0.61) using the serum levels of the 6 proteins at various GAs from women with normal uncomplicated pregnancies (n = 10 for training and n = 6 for validation). In pregnancies complicated by PE (n = 14), the EN model was not (R2 = -0.17) associated with GA at sampling in PE. Statistically significant deviations from the normal GA EN model estimations were observed in PE-associated pregnancies between GAs of 16-30 weeks (P = 0.01). The EN model developed with 5 proteins (ELA excluded due to the lack of robustness of the mouse ELA essay) performed similarly on normal human (R2 = 0.68) and WT mouse (R2 = 0.85) pregnancies. Disruptions of this model were observed in both human PE-associated (human: R2 = 0.27) and mouse HO-1 Het (mouse: R2 = 0.30) pregnancies. LEP out performed sFlt-1 and PlGF in differentiating impending PE at early human and late mouse gestations. Conclusions: As revealed in both human and mouse GA EN analyses, temporal serological placenta-related protein patterns are tightly regulated throughout normal human pregnancies and can be significantly disrupted in pathologic PE states. LEP changes earlier during gestation than the well-established late GA PE biomarkers (sFlt-1 and PlGF). Our HO-1 Het mouse analysis provides direct evidence of the causative action of HO-1 deficiency in LEP upregulation in a PE-like murine model. Therefore, longitudinal analyses of pregnancy-related protein patterns in sera, may not only help in the exploration of underlying PE pathophysiology but also provide better clinical utility in PE assessment.

Clinical Presentation of Preeclampsia and the Diagnostic Value of Proteins and Their Methylation Products as Biomarkers in Pregnant Women with Preeclampsia and Their Newborns

Article

Full-text available

Jun 2018
J Pregnancy

Preeclampsia (PE) is a disorder which affects 1-10% of pregnant women worldwide. It is characterised by hypertension and proteinuria in the later stages of gestation and can lead to maternal and perinatal morbidity and mortality. Other than the delivery of the foetus and the removal of the placenta, to date there are no therapeutic approaches to treat or prevent PE. It is thus only possible to reduce PE-related mortality through early detection, careful monitoring, and treatment of the symptoms. For these reasons the search for noninvasive, blood-borne, or urinary biochemical markers that could be used for the screening, presymptomatic diagnosis, and prediction of the development of PE is of great urgency. So far, a number of biomarkers have been proposed for predicting PE, based on pathophysiological observations, but these have mostly proven to be unreliable and inconsistent between different studies. The clinical presentation of PE and data gathered for the biochemical markers placental growth factor (PlGF), soluble Feline McDonough Sarcoma- (fms-) like tyrosine kinase-1 (sFlt-1), asymmetric dimethylarginine (ADMA), and methyl-lysine is being reviewed with the aim of providing both a clinical and biochemical understanding of how these biomarkers might assist in the diagnosis of PE or indicate its severity.

Neurodevelopmental Disruptions in Children of Preeclamptic Mothers: Pathophysiological Mechanisms and Consequences

Article

Full-text available

Mar 2024
INT J MOL SCI

Preeclampsia (PE) is a multisystem disorder characterized by elevated blood pressure in the mother, typically occurring after 20 weeks of gestation and posing risks to both maternal and fetal health. PE causes placental changes that can affect the fetus, particularly neurodevelopment. Its key pathophysiological mechanisms encompass hypoxia, vascular and angiogenic dysregulation, inflammation, neuronal and glial alterations, and disruptions in neuronal signaling. Animal models indicate that PE is correlated with neurodevelopmental alterations and cognitive dysfunctions in offspring and in humans, an association between PE and conditions such as cerebral palsy, autism spectrum disorder, attention deficit hyperactivity disorder, and sexual dimorphism has been observed. Considering the relevance for mothers and children, we conducted a narrative literature review to describe the relationships between the pathophysiological mechanisms behind neurodevelopmental alterations in the offspring of PE mothers, along with their potential consequences. Furthermore, we emphasize aspects pertinent to the prevention/treatment of PE in pregnant mothers and alterations observed in their offspring. The present narrative review offers a current, complete, and exhaustive analysis of (i) the pathophysiological mechanisms that can affect neurodevelopment in the children of PE mothers, (ii) the relationship between PE and neurological alterations in offspring, and (iii) the prevention/treatment of PE.

Repeat placental growth factor-based testing in women with suspected preterm pre-eclampsia (PARROT-2): a multicentre, parallel-group, superiority, randomised controlled trial

Article

Feb 2024
LANCET

Accuracy of placental growth factor alone or in combination with soluble fms-like tyrosine kinase-1 or maternal factors in detecting preeclampsia in asymptomatic women in the second and third trimesters: a systematic review and meta-analysis

Article

Mar 2023
AM J OBSTET GYNECOL

Objective: This study aimed to: (1) identify all relevant studies reporting on the diagnostic accuracy of maternal circulating placental growth factor) alone or as a ratio with soluble fms-like tyrosine kinase-1), and of placental growth factor-based models (placental growth factor combined with maternal factors±other biomarkers) in the second or third trimester to predict subsequent development of preeclampsia in asymptomatic women; (2) estimate a hierarchical summary receiver-operating characteristic curve for studies reporting on the same test but different thresholds, gestational ages, and populations; and (3) select the best method to screen for preeclampsia in asymptomatic women during the second and third trimester of pregnancy by comparing the diagnostic accuracy of each method. Data sources: A systematic search was performed through MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform databases from January 1, 1985 to April 15, 2021. Study eligibility criteria: Studies including asymptomatic singleton pregnant women at >18 weeks' gestation with risk of developing preeclampsia were evaluated. We included only cohort or cross-sectional test accuracy studies reporting on preeclampsia outcome, allowing tabulation of 2×2 tables, with follow-up available for >85%, and evaluating performance of placental growth factor alone, soluble fms-like tyrosine kinase-1- placental growth factor ratio, or placental growth factor-based models. The study protocol was registered on the International Prospective Register Of Systematic Reviews (CRD 42020162460). Methods: Because of considerable intra- and interstudy heterogeneity, we computed the hierarchical summary receiver-operating characteristic plots and derived diagnostic odds ratios, β, θi, and Λ for each method to compare performances. The quality of the included studies was evaluated by the QUADAS-2 tool. Results: The search identified 2028 citations, from which we selected 474 studies for detailed assessment of the full texts. Finally, 100 published studies met the eligibility criteria for qualitative and 32 for quantitative syntheses. Twenty-three studies reported on performance of placental growth factor testing for the prediction of preeclampsia in the second trimester, including 16 (with 27 entries) that reported on placental growth factor test alone, 9 (with 19 entries) that reported on the soluble fms-like tyrosine kinase-1-placental growth factor ratio, and 6 (16 entries) that reported on placental growth factor-based models. Fourteen studies reported on performance of placental growth factor testing for the prediction of preeclampsia in the third trimester, including 10 (with 18 entries) that reported on placental growth factor test alone, 8 (with 12 entries) that reported on soluble fms-like tyrosine kinase-1-placental growth factor ratio, and 7 (with 12 entries) that reported on placental growth factor-based models. For the second trimester, Placental growth factor-based models achieved the highest diagnostic odds ratio for the prediction of early preeclampsia in the total population compared with placental growth factor alone and soluble fms-like tyrosine kinase-1-placental growth factor ratio (placental growth factor-based models, 63.20; 95% confidence interval, 37.62-106.16 vs soluble fms-like tyrosine kinase-1-placental growth factor ratio, 6.96; 95% confidence interval, 1.76-27.61 vs placental growth factor alone, 5.62; 95% confidence interval, 3.04-10.38); placental growth factor-based models had higher diagnostic odds ratio than placental growth factor alone for the identification of any-onset preeclampsia in the unselected population (28.45; 95% confidence interval, 13.52-59.85 vs 7.09; 95% confidence interval, 3.74-13.41). For the third trimester, Placental growth factor-based models achieved prediction for any-onset preeclampsia that was significantly better than that of placental growth factor alone but similar to that of soluble fms-like tyrosine kinase-1-placental growth factor ratio (placental growth factor-based models, 27.12; 95% confidence interval, 21.67-33.94 vs placental growth factor alone, 10.31; 95% confidence interval, 7.41-14.35 vs soluble fms-like tyrosine kinase-1-placental growth factor ratio, 14.94; 95% confidence interval, 9.42-23.70). Conclusion: Placental growth factor with maternal factors ± other biomarkers determined in the second trimester achieved the best predictive performance for early preeclampsia in the total population. However, in the third trimester, placental growth factor-based models had predictive performance for any-onset preeclampsia that was better than that of placental growth factor alone but similar to that of soluble fms-like tyrosine kinase-1-placental growth factor ratio. Through this meta-analysis, we have identified a large number of very heterogeneous studies. Therefore, there is an urgent need to develop standardized research using the same models that combine serum placental growth factor with maternal factors ± other biomarkers to accurately predict preeclampsia. Identification of patients at risk might be beneficial for intensive monitoring and timing delivery.

Soluble suppression of tumorigenicity-2 in pregnancy with a small-for-gestational-age fetus and with preeclampsia

Article

Full-text available

Dec 2022

Objective Preeclampsia and fetal growth disorders are pregnancy-specific conditions that share common pathophysiological mechanisms. Yet, why some patients develop preeclampsia while others experience fetal growth restriction, or a combination of both clinical presentations, is unknown. We propose that the difference in severity of the maternal inflammatory response can contribute to the clinical phenotypes of preeclampsia vs. small for gestational age (SGA). To assess this hypothesis, we measured maternal plasma concentrations of the soluble isoform of suppression of tumorigenicity-2 (sST2), a member of the interleukin-1 receptor family that buffers proinflammatory responses. Previous reports showed that serum sST2 concentrations rise in the presence of intravascular inflammation and Th1-type immune responses and are significantly higher in patients with preeclampsia compared to those with normal pregnancy. The behavior of sST2 in pregnancies complicated by SGA has not been reported. This study was conducted to compare sST2 plasma concentrations in normal pregnancies, in those with preeclampsia, and in those with an SGA fetus. Methods This retrospective cross-sectional study included women with an SGA fetus (n = 52), women with preeclampsia (n = 106), and those with normal pregnancy (n = 131). Maternal plasma concentrations of sST2 were determined by enzyme-linked immunosorbent assay. Doppler velocimetry of the uterine and umbilical arteries was available in a subset of patients with SGA (42 patients and 43 patients, respectively). Results (1) Women with an SGA fetus had a significantly higher median plasma concentration of sST2 than normal pregnant women (p = .008); (2) women with preeclampsia had a significantly higher median plasma concentration of sST2 than those with normal pregnancy (p < .001) and those with an SGA fetus (p < .001); (3) patients with SGA and abnormal uterine artery Doppler velocimetry had a higher median plasma concentration of sST2 than controls (p < .01) and those with SGA and normal uterine artery Doppler velocimetry (p = .02); (4) there was no significant difference in the median plasma sST2 concentration between patients with SGA who had normal uterine artery Doppler velocimetry and controls (p = .4); (5) among patients with SGA, those with abnormal and those with normal umbilical artery Doppler velocimetry had higher median plasma sST2 concentrations than controls (p = .001 and p = .02, respectively); and (6) there was no significant difference in the median plasma sST2 concentrations between patients with SGA who did and those who did not have abnormal umbilical artery Doppler velocimetry (p = .06). Conclusions Preeclampsia and disorders of fetal growth are conditions characterized by intravascular inflammation, as reflected by maternal plasma concentrations of sST2. The severity of intravascular inflammation is highest in patients with preeclampsia.

Preeclampsia at term can be classified into 2 clusters with different clinical characteristics and outcomes based on angiogenic biomarkers in maternal blood

Article

Full-text available

Nov 2022
AM J OBSTET GYNECOL

Background An anti-angiogenic state has emerged as a mechanism of disease in preeclampsia. Angiogenic biomarkers are utilized in the risk assessment of this syndrome, particularly of early disease. The role of an anti-angiogenic state in late preeclampsia is unclear. Objective To determine the prevalence, characteristics, and clinical significance of angiogenic/anti-angiogenic factor abnormalities in women with preeclampsia stratified according to gestational age at delivery. Study Design Two studies were conducted: 1) a longitudinal nested case-control study comprising women with preeclampsia (n=151) and a control group (n=540); and 2) a case series of patients with preeclampsia (n=452). In patients with preeclampsia, blood was collected at the time of diagnosis and at every admission. Plasma concentrations of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were determined by enzyme-linked immunosorbent assays. An abnormal angiogenic profile was defined as a plasma ratio of the PlGF and sFlt-1 multiple of the median below the 10th percentile for gestational age based on values derived from the longitudinal study. The proportion of patients diagnosed with preeclampsia with an abnormal angiogenic profile was determined in the case-series participants as stratified by gestational age at delivery into early (≤ 34 weeks), intermediate (34.1–36.9 weeks), and term (≥37 weeks) preeclampsia. The demographics, clinical characteristics, and pregnancy outcomes of preeclampsia with and without an abnormal angiogenic profile were compared. Results 1) The prevalence of an abnormal angiogenic profile was higher in preterm compared to term preeclampsia (for early, intermediate, and term in the case-control study: 90%, 100%, and 39%; for the case series: 98%, 80%, and 55%, respectively); 2) women with preeclampsia at term and an abnormal angiogenic profile were more frequently nulliparous (57% vs 35%), less likely to smoke (14% vs 26%), at greater risk for maternal (14% vs 5%) or neonatal (7% vs 1%) complications, and more often had placental lesions consistent with maternal vascular malperfusion (42% vs 23%; all, p<0.05) than those without an abnormal profile; 3) women with preeclampsia at term and a normal angiogenic profile had a higher frequency of chronic hypertension (36% vs 21%) and were more likely to be obese, greater than class II (41% vs 23%) than those with an abnormal profile (both, p<0.05). Conclusion Patients with early preeclampsia had an abnormal angiogenic profile in virtually all cases, whereas only 50% of women with preeclampsia at term had such perturbations. The profile of angiogenic biomarkers can be used to classify patients with preeclampsia at term, based on mechanisms of disease, into two clusters, which have different demographics, clinical characteristics, and risks for adverse maternal and neonatal outcomes. These findings provide a simple approach to classify preeclampsia at term and have implications for future clinical care and research.

Association of Fetal Sex with Angiogenic Factors in Normotensive and Hypertensive Pregnancy States

Article

Jul 2022

Objectives With the incorporation of angiogenic biomarkers into clinical practice, identification of potential modifiers of the angiogenic profile, including fetal sex, is essential. Study Design: In this retrospective cohort analysis, patients with hypertensive disorders of pregnancy (HDP) and normotensive pregnancies were enrolled upon admission to Labor and Delivery. Blood samples for angiogenic factors were assessed using an automated platform. Clinical and demographic information was abstracted from each patient’s medical records. Main Outcome Measures: Evaluate soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF) levels and their ratio in relation to fetal sex in patients with normotensive pregnancies compared to those with HDP. Results A total of 617 patients were analyzed (299 normotensive, 113 gestational hypertensive, 71 chronic hypertensive, and 134 preeclamptic patients). There was no difference between the number of patients who had a male fetus among preeclampsia and normotensive parturients (56.0% vs. 50.2%, p = 0.26). Normotensive patients carrying a male fetus had significantly higher sFlt1 (3168 [IQR: 2160-4945] vs. 2678 [IQR: 1752-4271]; p = 0.01) and sFlt1/PlGF ratios (18 [IQR: 7-44] vs. 12 [IQR: 5-30]; p = 0.01) in comparison to pregnant patients carrying a female fetus. This difference between fetal sexes was not observed in the angiogenic profile of patients with HDP. Conclusions Our study of primarily Black, obese patients demonstrates that normotensive patients carrying a male fetus have a significantly higher sFlt1 and sFlt1/PlGF ratio as compared to those carrying a female fetus at term gestation. Fetal sex should be considered as a confounder when studying angiogenic factors in normotensive pregnant patients.

Arterial stiffness and pulsatile hemodynamics in pregnancy and pregnancy-related vascular complications

Chapter

Jan 2022

Stella S Daskalopoulou

In healthy pregnancies, maternal adaptations occur to accommodate both maternal and fetal metabolic demands. Systemic vasodilation and increased vascular compliance occur early in the first trimester, leading to decreased systemic vascular resistance that reaches a nadir in the second trimester. Consequently, increases in cardiac output, renin–angiotensin–aldosterone system activity, and plasma volume occur. The vascular and hematological changes result in a U-shaped curve in blood pressures, large artery stiffness (carotid-femoral pulse wave velocity, cfPWV), and wave reflection, reaching a nadir in the second trimester. The demands of the developing fetus progressively increase with gestation; thus, vascular complications usually occur in the second-half of pregnancy. In this context, in preeclampsia, a potentially severe hypertensive disorder of pregnancy, impaired vascular responses are observed: blood pressures, cfPWV, and wave reflection exhibit a continuous increase from the first trimester to the end of pregnancy and beyond, rather than a U-shaped curve. Compared to normotensive pregnancies, arterial stiffness is significantly higher at the time of preeclampsia diagnosis, and its magnitude of increase is correlated with preeclampsia severity. Overall, vascular maladaptations in preeclampsia lead to failure to accommodate the increased demands of gestation, with devastating consequences for both the mother and fetus. This chapter reviews the vascular adaptations in pregnancy and the role of vascular dysfunction in the pathogenesis of hypertensive disorders of pregnancy.

Preeclampsia and eclampsia: the conceptual evolution of a syndrome

Article

Feb 2022
AM J OBSTET GYNECOL

Preeclampsia, one of the most enigmatic complications of pregnancy, is considered a pregnancy-specific disorder caused by the placenta and cured only by delivery. This article traces the condition from its origins—once thought to be a disease of the central nervous system, recognized by the occurrence of seizures (ie, eclampsia)—to the present time when preeclampsia is conceptualized primarily as a vascular disorder. We review the epidemiologic data that led to the recommendation to use diastolic hypertension and proteinuria as diagnostic criteria, as their combined presence was associated with an increased risk of fetal death and the birth of small-for-gestational-age neonates. However, preeclampsia is a multisystemic disorder with protean manifestations, and the condition can be present even in the absence of hypertension and proteinuria. Toxins gaining access to the maternal circulation have been proposed to mediate the clinical manifestations—hence, the term “toxemia of pregnancy,” which was used for several decades. The search for putative toxins has challenged investigators for more than a century, and a growing body of evidence suggests that products of an ischemic or a stressed placenta are responsible for the vascular changes that characterize this syndrome. The discovery that the placenta can produce antiangiogenic factors, which regulate endothelial cell function and induce intravascular inflammation, has been a major step forward in the understanding of preeclampsia. We view the release of antiangiogenic factors by the placenta as an adaptive response to improve uterine perfusion by modulating endothelial function and maternal cardiovascular performance. However, this homeostatic response can become maladaptive and lead to damage of target organs during pregnancy or the postpartum period. Early-onset preeclampsia has many features in common with atherosclerosis, whereas late-onset preeclampsia seems to result from a mismatch of fetal demands and maternal supply, that is, a metabolic crisis. Preeclampsia, as it is understood today, is essentially vascular dysfunction unmasked or caused by pregnancy. A subset of patients diagnosed with preeclampsia are at greater risk of the subsequent development of hypertension, ischemic heart disease, heart failure, vascular dementia, and end-stage renal disease. However, these adverse events may be the result of a preexisting vascular pathologic process; it is not known if the occurrence of preeclampsia increases the baseline risk. Therefore, the understanding, prediction, prevention, and treatment of preeclampsia are healthcare priorities.

Association between serum placental growth factor and vascular endothelial function in hyprtensive disorders complicating pregnancy

Article

Dec 2021

Hypertensive disorders complicating pregnancy (HDCP) is a systemic disease among pregnant women. Therefore, the prevention and prediction of hypertension during pregnancy are critical. This study aimed to clarify whether the vascular endothelial function of women with gestational hypertension was linked to placental growth factor. A total of 200 pregnant women were enrolled in our study and subsequently divided into two groups: the HDCP group and the normal pregnancy controls. The levels of serum placental growth factor, as well as plasma endothelin-1 and nitric oxide, between the two groups were measured. In addition, the endothelial function indexes, including pressure-strain elasticity coefficient (EP), the common carotid stiffness index (β), arterial compliance, single-point pulsed-wave velocity, and augment index (AI) of bilateral common carotid arteries, were compared between the HDCP and control groups using the echo tracking technique. In our study, the level of placental growth factor in the HDCP group was significantly lower than the control group. Furthermore, our results clarified that endothelin-1 increased while nitric oxide decreased in the HDCP group compared with the control group. On the other hand, we found that EP, β, pulsed-wave velocity and augment index values were significantly higher in the HDCP group than in the control group (P < 0.001). However, the value of arterial compliance was significantly decreased in patients of the HDCP group compared with the control group (P < 0.001). In conclusion, the association between serum placental growth factor and vascular endothelial function in HDCP could serve as a more accurate predictive factor of pregnant hypertension.

The Placental Circulations

Chapter

Jan 2022

In this chapter, two placental circulations are considered. First, the angioarchitecture of the villous trees is described and discussed in the context of the molecular regulation of placental vasculogenesis and angiogenesis. Then, adaptations of the maternal uterine arterial supply during pregnancy are covered, and the implications of deficient spiral artery remodeling for placental morphology and function addressed. Finally, the lobular arrangement of the villous trees and the interrelationships of the two circulations for effective maternal-fetal exchange are discussed.

Alpha-1 Antitrypsin MZ Heterozygosity Is an Endotype of Chronic Obstructive Pulmonary Disease

Article

Nov 2021

Rationale: Multiple studies have demonstrated an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygous carriers of the alpha-1 antitrypsin Z allele. However, it is not known if MZ subjects with COPD are phenotypically different compared to non-carriers (MM genotype) with COPD. We hypothesized that MZ subjects with COPD have different clinical features compared to MM subjects with COPD. Methods: Genotypes of SERPINA1 were ascertained from whole genome sequencing data in three independent studies. We compared outcomes between MM and MZ subjects with COPD in each study and combined the results in a meta-analysis. We performed longitudinal and survival analyses to compare outcomes in MM and MZ subjects with COPD over time. Results: We included 290 MZ subjects with COPD and 6,184 MM subjects with COPD across the three studies. MZ subjects had lower FEV1 % predicted and greater quantitative emphysema on chest CT scans compared to MM subjects. In a meta-analysis, FEV1 was 3.9% lower (95% CI -6.55, -1.26) and emphysema (percent of lung attenuation areas < -950HU) was 4.14% greater (95% CI 1.44, 6.84) in MZ subjects. We found one gene, PGF, differentially expressed in lung tissue from one study between MZ subjects compared to MM subjects. Conclusions: Carriers of the alpha-1 antitrypsin Z allele (MZ heterozygotes) with COPD had lower lung function and more emphysema compared to MM subjects with COPD. Taken with the subtle differences in gene expression between the two groups, our findings suggest that MZ subjects represent an endotype of COPD.

A comparative study of two immunoassays of maternal placental growth factor

Article

Apr 2021

Circulating maternal levels of placental growth factor correlates well with placental function and numerous studies advocate its role to help rule-out preterm pre-eclampsia. A number of automated immunoassay platforms to quantify placental growth factors are currently available. The aim of this study was to highlight the importance of developing and validating appropriate reference ranges and clinical cut-offs for immunoassays, by comparing the results obtained from two different immunoassays of placental growth factor; the Quantikine® ELISA and the automated Triage® test. This was a secondary subgroup analysis of samples collected as part of a prospective cross-sectional study of placental growth factors in twin pregnancy. Consenting pregnant women with a twin pregnancy, across a variety of gestations, had a single blood sample taken at a one-time point only during their pregnancy. The plasma was initially biobanked and then later analysed in batches using both immunoassays. Although the placental growth factor values of the two immunoassays correlated well (r = 0.88, n = 178, p < .001), the actual results obtained were significantly different (mean difference 238.1 pg/ml). Poor concordance between the two immunoassays was also present, with the Triage® test recording 36 cases as <100 pg/ml whereas the Quantikine® ELISA identified only 4 as <100 pg/ml. Biomarker levels may vary significantly between different immunoassay platforms, highlighting the importance of developing validated clinical cut-offs for any automated immunoassay before its clinical application. These differences need to be understood to facilitate clinical utility given that placental growth factor testing is likely to be introduced into widespread clinical practice.

Concordance-analysis and evaluation of different diagnostic algorithms used in first trimester screening for late-onset preeclampsia

Article

Apr 2020

Objective: Concordance-analysis and evaluation of existing algorithms detecting late-onset preeclampsia during first trimester screening Methods: Retrospective cohort study investigating risk algorithms of late-onset preeclampsia during first trimester screening in a German prenatal center. Three previously developed algorithms including anamnestic factors (Apriori) and biophysical markers (BioM) were investigated by using detection rates (DR) with fixed FPR 10% and fixed cutoff >1:100. Furthermore, we set up a concordance-analysis of test results in late-onset preeclampsia cases to examine the effect of influencing factors and to detect potential weaknesses of the algorithms. Therefore, we modeled the probability of discordances as a function of the influencing factors based on a logistic regression, that was fitted using a Bayesian approach. Results: 6,113 pregnancies were considered, whereof 700 have been excluded and 5,413 pregnancies were analyzed. 98 (1.8%) patients developed preeclampsia (79 late-onsets, 19 early-onsets). The Apriori-algorithm reaches a DR of 34.2%, by adding BioM (MAP and UtA-PI) the DR improves to 57.0% (FPR of 10%). In concordance-analysis of Apriori algorithm and Apriori+BioM algorithms, influencing factor BMI<25 increases the chance of discordances sigificantly. Additional, in the subgroup of late-onset preeclampsias with BMI<25 the DR is higher in Apriori+BioM algorithms than in Apriori algorithm alone. If both compared algorithms include BioM, influencing factor MAP decreases the chance of discordances significantly. All other tested influencing factors do not have a statistically significant effect on discordances Conclusion: Normal-weight patients benefit more from the integration of MAP and UtA-PI compared to overweight/obese patients.

Changes in pregnancy-related serum biomarkers early in gestation are associated with later development of preeclampsia

Article

Full-text available

Mar 2020
PLOS ONE

Background Placental protein expression plays a crucial role during pregnancy. We hypothesized that: (1) circulating levels of pregnancy-associated, placenta-related proteins throughout gestation reflect the temporal progression of the uncomplicated, full-term pregnancy, and can effectively estimate gestational ages (GAs); and (2) preeclampsia (PE) is associated with disruptions in these protein levels early in gestation; and can identify impending PE. We also compared gestational profiles of proteins in the human and mouse, using pregnant heme oxygenase-1 (HO-1) heterozygote (Het) mice, a mouse model reflecting PE-like symptoms. Methods Serum levels of placenta-related proteins–leptin (LEP), chorionic somatomammotropin hormone like 1 (CSHL1), elabela (ELA), activin A, soluble fms-like tyrosine kinase 1 (sFlt-1), and placental growth factor (PlGF)–were quantified by ELISA in blood serially collected throughout human pregnancies (20 normal subjects with 66 samples, and 20 subjects who developed PE with 61 samples). Multivariate analysis was performed to estimate the GA in normal pregnancy. Mean-squared errors of GA estimations were used to identify impending PE. The human protein profiles were then compared with those in the pregnant HO-1 Het mice. Results An elastic net-based gestational dating model was developed (R² = 0.76) and validated (R² = 0.61) using serum levels of the 6 proteins measured at various GAs from women with normal uncomplicated pregnancies. In women who developed PE, the model was not (R² = -0.17) associated with GA. Deviations from the model estimations were observed in women who developed PE (P = 0.01). The model developed with 5 proteins (ELA excluded) performed similarly from sera from normal human (R² = 0.68) and WT mouse (R² = 0.85) pregnancies. Disruptions of this model were observed in both human PE-associated (R² = 0.27) and mouse HO-1 Het (R² = 0.30) pregnancies. LEP outperformed sFlt-1 and PlGF in differentiating impending PE at early human and late mouse GAs. Conclusions Serum placenta-related protein profiles are temporally regulated throughout normal pregnancies and significantly disrupted in women who develop PE. LEP changes earlier than the well-established biomarkers (sFlt-1 and PlGF). There may be evidence of a causative action of HO-1 deficiency in LEP upregulation in a PE-like murine model.

Placental Production of Peptide, Steroid, and Lipid Hormones

Chapter

Jan 2020

First trimester serum angiogenic and anti-angiogenic factors in women with chronic hypertension for the prediction of preeclampsia

Article

Nov 2019
AM J OBSTET GYNECOL

Background: An imbalance between angiogenic and antiangiogenic factors is thought to be a central pathogenetic mechanism in preeclampsia. In pregnancies that subsequently develop preeclampsia the maternal serum concentration of the angiogenic placental growth factor (PLGF) is decreased from as early as the first trimester of pregnancy and the concentration of the antiangiogenic soluble fms-like tyrosine kinase-1 (sFLT-1) is increased in the last few weeks before the clinical presentation of the disease. Chronic hypertension, which complicates 1-2% of pregnancies, is the highest risk factor for development of preeclampsia among all other factors in maternal demographic characteristics and medical history. Two previous studies in women with chronic hypertension reported that first-trimester serum PLGF and sFLT-1 were not significantly different between those that developed superimposed preeclampsia and those that did not, whereas a third study reported that concentrations of PLGF were decreased. Objective: To investigate whether in women with chronic hypertension serum concentrations of PLGF and sFLT-1 and sFLT-1/PLGF ratio at 11+0 to 13+6 weeks' gestation are different between those that developed superimposed preeclampsia and those that did not and to compare these values to those in normotensive controls. Study design: The study population comprised of 650 women with chronic hypertension, including 202 that developed superimposed preeclampsia and 448 that did not develop preeclampsia, and 142 normotensive controls. Maternal serum concentration of PLGF and sFLT-1 were measured by an automated biochemical analyzer and converted into multiples of the expected median (MoM) using multivariate regression analysis in the control group. Comparisons of PLGF, sFLT-1 and sFLT-1/PLGF ratio in MoM values between the two groups of chronic hypertension and the controls were made by the ANOVA or the Kruskal-Wallis test. Results: In the group of chronic hypertension that developed preeclampsia, compared to those that did not develop preeclampsia, there were significantly lower median concentrations of serum PLGF MoM (0.904, interquartile range (IQR) 0.771-1.052 vs. 0.948, IQR 0.814-1.093; p=0.014) and sFLT-1 MoM (0.895, IQR 0.760-1.033 vs 0.938, IQR 0.807-1.095; p=0.013) and they were both lower than in the normotensive controls (1.009, IQR 0.901-1.111 and 0.991, IQR 0.861-1.159, respectively; P<0.01 for both). There were no significant differences between the three groups in sFLT-1 / PLGF ratio. In women with chronic hypertension serum PLGF and sFLT-1 provided poor prediction of superimposed preeclampsia (area under the curve 0.567, 95% confidence interval (CI) 0.537-0.615 and 0.546, 95% CI 0.507-0.585, respectively). Conclusions: Women with chronic hypertension, and particularly those who subsequently developed preeclampsia, have reduced first trimester concentrations of both PLGF and sFLT-1.

Reference centiles for maternal placental growth factor levels at term from a low-risk population

Article

Aug 2019
PLACENTA

Introduction: Placental growth factor (PLGF) is a biomarker of placental function. The aim of this study was to define reference ranges for maternal PLGF levels in a normotensive cohort ≥36 + 0 weeks. Method: Prospective observational data from Mater Mothers' Hospital, Brisbane. PLGF levels were measured in women at ≥36 + 0 weeks with singleton, non-anomalous pregnancies. Women with hypertension and fetal growth restriction were excluded. PLGF (pg/mL) was assayed using DELFIA® Xpress (PerkinElmer Inc). The Generalised Additive Model for Location, Shape and Scale (GAMLSS) method was used for the calculation of gestational age-adjusted centiles. Data analysis was performed with Stata 13 (StataCorp, LLC) and R software (R Foundation for Statistical Computing, Vienna, Austria). In all women, PLGF was measured within 2 weeks of delivery. Results: The study cohort comprised of 845 women (36 weeks n = 73, 37 weeks n = 230, 38 weeks n = 214, 39 weeks n = 172, 40 weeks n = 115, 41weeks n = 41). PLGF levels were negatively correlated with gestational age (r = -0.20, p < 0.001). Median PLGF levels dropped significantly from 36 weeks to 41 weeks (169.0 pg/mL to 96.6 pg/mL, p < 0.001). Gestational age specific maternal PLGF centiles were reported using fractional polynomial additive term and Box-Cox t distribution. PLGF did not perform adequately as a predictive test for adverse perinatal outcomes (AUC <0.6). Discussion: We have created gestational centile reference ranges for maternal PLGF from a normotensive cohort. These novel data suggest maternal PLGF levels decline ≥36 + 0 weeks. The utility of PLGF as a predictor of adverse perinatal outcomes at term, should be further investigated with clinical trials.

Adult Pgf−/− mice behaviour and neuroanatomy are altered by neonatal treatment with recombinant placental growth factor

Article

Full-text available

Jun 2019

Offspring of preeclamptic pregnancies have cognitive alterations. Placental growth factor (PGF), is low in preeclampsia; reduced levels may affect brain development. PGF-null mice differ from normal congenic controls in cerebrovasculature, neuroanatomy and behavior. Using brain imaging and behavioral testing, we asked whether developmentally asynchronous (i.e. neonatal) PGF supplementation alters the vascular, neuroanatomic and/or behavioral status of Pgf−/− mice at adulthood. C57BL/6-Pgf−/− pups were treated intraperitoneally on postnatal days 1–10 with vehicle or PGF at 10 pg/g, 70 pg/g or 700 pg/g. These mice underwent behavioral testing and perfusion for MRI and analysis of retinal vasculature. A second cohort of vehicle- or PGF-treated mice was perfused for micro-CT imaging. 10 pg/g PGF-treated mice exhibited less locomotor activity and greater anxiety-like behavior relative to vehicle-treated mice. Depressive-like behavior showed a sex-specific, dose-dependent decrease and was lowest in 700 pg/g PGF-treated females relative to vehicle-treated females. Spatial learning did not differ. MRI revealed smaller volume of three structures in the 10 pg/g group, larger volume of seven structures in the 70 pg/g group and smaller volume of one structure in the 700 pg/g group. No cerebral or retinal vascular differences were detected. Overall, neonatal PGF replacement altered behavior and neuroanatomy of adult Pgf−/− mice.

Placenta Growth Factor and Sflt-1 As Biomarkers in Ischemic Heart Disease and Heart Failure: A Review

Article

Jun 2019

Coronary heart disease (CHD) and heart failure (HF) produce significant morbidity/mortality but identifying new biomarkers could help in the management of each. In this article, we summarize the molecular regulation and biomarker potential of PIGF and sFlt-1 in CHD and HF. PlGF is elevated during ischemia and some studies have shown PlGF, sFlt-1 or PlGF:sFlt-1 ratio, when used in combination with standard biomarkers, strengthens predictions of outcomes. sFlt-1 and PlGF are elevated in HF with sFlt-1 as a stronger predictor of outcomes. Although promising, we discuss additional study criteria needed to confirm the clinical usefulness of PlGF or sFlt-1 in the detection and management of CHD or HF.

Longitudinal circulating placental growth factor (PlGF) and soluble FMS-like tyrosine kinase-1 (sFlt-1) concentrations during pregnancy in Asian women: a prospective cohort study

Article

Full-text available

May 2019

Objectives To analyse the placental growth factor (PlGF) and soluble FMS-like tyrosine kinase-1 (sFlt-1) trends in the normal pregnant Asian population in Singapore. Design A prospective study was conducted. Setting The largest tertiary hospital in Singapore. Methods Women with single viable pregnancies, less than 14 weeks of gestation, were recruited between September 2010 and November 2013 in KK Women’s and Children’s Hospital. They were followed up from recruitment till their postnatal discharge from the hospital. There were four antenatal visits: gestational age (GA) less than 14+0 weeks of gestation (V1), GA 18+0 to 22+0 weeks (V2), GA 28+0 to 32+0 weeks (V3) and GA 34+0 and above (V4). Serum biochemical markers (sFlt-1, PlGF) were measured at each visit. Results There were 934 participants in the study, of which 674 had normal pregnancy outcomes. The sFlt-1 remained relatively constant till GA 28–32 weeks before it increased (p<0.001). The sFlt-1 levels increased earlier before 30 weeks’ of gestation among the Malay participants and the other ethnicities. For PlGF, the levels increased from the first to the third trimester, peaking at 30–32 weeks before decreasing (p<0.001). Its serum levels significantly differed among the Indian participants and other ethnicities as compared with the Malay and Chinese participants at V3 and V4, (p=0.04 and p<0.001, respectively). Conclusion There are significant differences in the PlGF and sFlt-1 concentrations during pregnancy between different ethnicities, which should be taken into consideration when using these references values for further research.

Physiopathology: Current Evidence and Clinical Practice

Chapter

Jan 2019

Fetal growth restriction (FGR) is a potential fetal threatening condition that may increase fetal and neonatal morbidity. Although an abnormal placental function is an underlying cause, FGR recognizes multifactorial factors. Impaired cytotrophoblastic invasion, spiral artery remodeling, and fetal-placental angiogenesis are important mechanisms involved in the development of FGR. The pathogenetic mechanisms of FGR are still far to be completely elucidated; however different soluble substances such as epidermal growth factor (EGF), vascular growth factor (VGFA), insulin growth factor (IGF), and placental growth factor (PlGF) act at cellular level and may altered placental function with subsequent development of FGR. Extracellular matrix such as decorin (DCN) plays important role in the control of collagen fibrillogenesis and matrix remodeling and regulates cytotrophoblastic proliferation, migration, and syncytium formation. Moreover, a decreased DCN expression during the first trimester is associated with small for gestational age (SGA) fetuses late in pregnancy. Angiogenic molecules such as angiopoietin and endothelin, one of the most potent vasoconstrictor agents known, may contribute to preeclampsia (PE), with or without FGR. The current chapter has also reviewed the role of epigenetics because genomic mechanisms may be responsible for 40–80% of fetal growth development. Genomic imprinting and DNA methylation play critical role in gene regulation, and transcription pathways related to organ development and metabolic function can be found in the placenta and cord blood from fetus and neonates affected by FGR. Imprinted genes are highly expressed in the placenta and regulate placental morphology and function. Insulin growth factor 2 (IGF2), the most intensively studied imprinted gene, and its role in the pathogenesis of FGR are described in details.

Research in Maternal Medicine

Chapter

Aug 2017

Health-centred research has changed hugely over the last ten years, from the importance of computing software to the NHS becoming more involved in research. The expectations of grant-awarding bodies, ethics committees and publishers have evolved and increased in many senses. This new edition is designed for trainee clinicians, not only those preparing for membership of the Royal College of Obstetricians and Gynaecologists (MRCOG) but also higher degree candidates and aspiring clinical academics. Chapter authors with extensive expertise make the path to embarking on research direct, straightforward and most importantly, fun and interesting; particularly aiming to support those who trained clinically and are now undertaking a research project or beginning an academic career. There remains no single book with so much relevant information gathered in a single, succinct volume. This edition now covers the wide spectrum of modern research methods for all specialities, with five supplementary chapters on major obstetric and gynaecological subspecialties.

ELABELA plasma concentrations are increased in women with late-onset preeclampsia

Article

Jun 2018

Objective: ELABELA is a newly discovered peptide hormone that appears to be implicated in the mechanisms leading to preeclampsia, independently of angiogenic factors. The aim of the current study was to investigate whether women with early- or late-onset preeclampsia have altered ELABELA plasma concentrations compared to gestational-age-matched normal pregnant women. Methods: This retrospective cross sectional study focused on the maternal plasma samples collected from 236 women with a singleton pregnancy who were allocated into the following groups: 1) early-onset preeclampsia (< 34 weeks of gestation, N = 56); 2) late-onset preeclampsia (≥ 34 weeks of gestation, N = 57); and 3) gestational-age-matched controls with a normal pregnancy [(< 34 weeks of gestation, N = 59); (≥ 34 weeks of gestation, N = 60)]. ELABELA plasma concentrations were determined using a validated enzyme immunoassay. Results: 1) ELABELA plasma concentrations are higher in patients with late-onset preeclampsia compared to those from gestational-age-matched controls with a normal pregnancy [median: 7.99 ng/mL (IQR, 3–11.19 ng/mL) versus median: 4.17 ng/mL (IQR, 5.3–13.95 ng/mL), p = 0.001]; 2) ELABELA plasma concentrations in patients with early-onset preeclampsia do not differ from those of normal pregnant women [median: 6.09 ng/mL (IQR, 2.8–10.66 ng/mL) versus median: 4.02 ng/mL (IQR, 3.26–7.49), p = 0.32]; and 3) ELABELA plasma concentrations are higher in patients with late-onset preeclampsia compared to those with early-onset preeclampsia [median: 7.99 ng/mL (IQR, 3–11.19 ng/mL) versus median: 6.09 ng/mL (IQR, 2.8–10.66 ng/mL), p = 0.01]. Conclusion: ELABELA plasma concentrations are higher in patients with late-onset preeclampsia than in those with a normal pregnancy. However, women with early-onset preeclampsia have similar ELABELA plasma concentrations to those with a normal pregnancy. These findings provide insight into the ELABELA axis during the human syndrome of preeclampsia. In addition, these data support the concept that different pathophysiologic mechanisms are implicated in early- and late- onset preeclampsia.

Endocrinology of Human Pregnancy and Fetal-Placental Neuroendocrine Development

Chapter

Feb 2018

Sam Mesiano

The success of pregnancy depends on (1) fertilization and successful implantation of the developing embryo into the endometrium; (2) development and function of the placenta; (3) adaptation of maternal physiology to accept the fetal allograft and satisfy its nutritional, metabolic, and physical demands; (4) appropriate growth and functional development of key organ and homeostatic systems in the fetus; and (5) proper timing of birth so that it occurs when the fetus is mature enough to survive outside the uterus. This chapter examines the complex array of hormonal interactions between the fetus, placenta, and mother that controls these processes.

sFlt-1/PLGF

Chapter

Mar 2018

Due to novel scientific knowledge about molecular pathomechanisms, there is a new understanding of preeclampsia as a placental disease. Angiogenic factors were shown to influence placentation, and in the last decade, intensive research emerged particularly the antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1) and the pro-angiogenic placental growth factor (PlGF) to be most relevant in this process. Technical efforts and the development of commercially available automated methods firstly enabled maternal serum measurements of these factors and the introduction into daily clinical use. In various clinical studies, the additional value of sFlt-1 and PlGF for diagnosis and even prediction of preeclampsia have been confirmed. This major advance firstly allows a better diagnosis and distinction of preeclampsia, a disease with an extremely heterogeneous clinical appearance, from various different gestation-associated symptoms or diseases. A more precise diagnosis and the feasibility of prediction opened new horizons in clinical management of preeclampsia. This article gives an overview about the latest scientific knowledge about the angiogenic factors sFlt-1 and PlGF and provides actual recommendations for its clinical use for suspected preeclampsia.

Placental Growth Factor: A review of literature and future applications

Article

Mar 2018

Prediction and prevention of pre-eclampsia in Asian subpopulation: Pre-eclampsia prediction in Asian women

Article

Feb 2018

The benefit of the early administration of aspirin to reduce preterm pre-eclampsia among screened positive European women from multivariate algorithmic approach (ASPRE trial) has opened an intense debate on the feasibility of universal screening. This review aims to assess the new perspectives in the combined screening of pre-eclampsia in the first trimester of pregnancy and the chances for prevention using low-dose aspirin with special emphasis on the particularities of the Asian population. PubMed, CENTRAL and Embase databases were searched from inception until 15 November 2017 using combinations of the search terms: preeclampsia, Asian, prenatal screening, early prediction, ultrasonography, pregnancy, biomarker, mean arterial pressure, soluble fms-like tyrosine kinase-1, placental growth factor, pregnancy-associated plasma protein-A and pulsatility index. This is not a systematic review or meta-analysis, so the risk of bias of the selected published articles and heterogeneity among the studies need to be considered. The prevalence of pre-eclampsia and serum levels of biochemical markers in Asian are different from Caucasian women; hence, Asian ethnicity needs to be corrected for in the algorithmic assessment of multiple variables to improve the screening performance. Aspirin prophylaxis may still be viable in Asian women, but resource implication needs to be considered. Asian ethnicity should be taken into account before implementing pre-eclampsia screening strategies in the region. The variables included can be mixed and matched to achieve an optimal performance that is appropriate for economical restriction in individual countries.

Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MGIsolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 88:9267-9271

Article

Full-text available

Nov 1991

A human cDNA coding for a protein related to the vascular permeability factor (VPF) was isolated from a term placenta cDNA library; we therefore named its product placenta growth factor (PlGF). PlGF is a 149-amino-acid-long protein and is highly homologous (53% identity) to the platelet-derived growth factor-like region of human VPF. Computer analyses reveal a putative signal peptide and two probable N-glycosylation sites in the PlGF protein, one of which is also conserved in human VPF. By using N-glycosidase F, tunicamycin, and specific antibodies produced in both chicken and rabbit, we demonstrate that PlGF, derived from transfected COS-1 cells, is actually N-glycosylated and secreted into the medium. In addition, PlGF, like VPF, proves to be a dimeric protein. Finally, a conditioned medium from COS-1 cells containing PlGF is capable of stimulating specifically the growth of CPA, a line of endothelial cells, in vitro.

Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants

Article

Full-text available

Nov 1986
Br J Obstet Gynaecol

An examination of the maternal vascular response to placentation shows that physiological changes in the placental bed normally extend from the decidua into the inner myometrium. In pre-eclampsia and in a proportion of pregnancies with small-for-gestational age infants (SGA) the physiological changes are restricted to the decidual segments alone. In addition, complete absence of physiological changes throughout the entire length of some spiral arteries is seen in pre-eclampsia and SGA. This new observation is confirmed in a study of basal plates of placentas from abnormal pregnancies. Intraluminal endovascular trophoblast may be seen in the placental bed spiral arteries in the third trimester in pre-eclampsia and SGA, a feature not seen beyond the second trimester in normal pregnancy. These findings point to a defect in the normal interaction between migratory trophoblast and maternal uterine tissues in pre-eclampsia and in SGA.

Smith Vascular endothelial growth factor receptor localization and activation in human trophoblast and choriocarcinoma cells

Article

Full-text available

Oct 1994

Vascular endothelial growth factor (VEGF; also known as vascular permeability factor) is a secreted angiogenic growth factor. It is highly specific for endothelial cells, and its receptor, the fms-like tyrosine kinase (flt), has been localized only to endothelial cells in vivo. Here we describe the expression of mRNA encoding flt in human trophoblast as revealed by in situ hybridization. This mRNA is highly expressed in the cytotrophoblast shell and columns and also highly expressed by the extravillous trophoblast (EVT) in the maternal decidua both in the first trimester and at term. The trophoblast-like choriocarcinoma cell line BeWo also expresses this receptor and the related receptor, kinase domain-containing receptor (KDR), which is also a receptor for VEGF. Treatment of the cell line BeWo with VEGF165 stimulated 3H-thymidine incorporation and tyrosine phosphorylation of MAP (mitogen-activated protein) kinase in a time- and dose-dependent fashion. This study is the first demonstration of the presence of flt on non-endothelial cells in vivo and suggests a role for VEGF in the growth and differentiation of cytotrophoblast at implantation.

FIt-I but not KDR/Flk-1 Tyrosine Kinase Is a Receptor for Placenta Growth Factor, Which Is Related to Vascular Endothelial Growth Factor1

Article

Full-text available

Mar 1996
Cell Growth Differ

Placenta Growth Factor (PIGF) is a new member of vascular endothelial growth factor (VEGF) family. Although VEGF binds Flt family Flt-1 and KDR/Flk-1 tyrosine kinases at high affinity for signal transduction, biological activities and the receptors of PIGF have not been extensively studied. Reverse transcription-PCR showed that PIGF-2, a subtype of PIGF-1 that bears a basic amino acid-rich domain, is more abundant than PIGF-1 and thus is the major subtype in human placenta. Using antibodies specific to PIGF-1 or -2 as markers, we obtained large amounts of PIGFs in the baculovirus expression system. PIGF-2 had growth-stimulatory activity on human umbilical vein endothelial cells and vascular permeability activity in the Miles assay at levels about 10-fold lower than those of VEGF. All PIGF-1 activities were lower than those of PIGF-2. Both PIGFs competed for the binding of 125I-labeled VEGF to Flt-1 receptor but not to KDR/Flk-1 expressed on NIH3T3 cells. Furthermore, 125I-labeled PIGF bound to Flt-1 at high affinity but not to KDR/Flk-1. Supporting the notion that PIGF can use only Flt-1 as a receptor, PIGF activated Flt-1 to autophosphorylate, whereas PIGF could not generate signals from KDR/Flk-1. These results indicate that Flt-1, but not KDR/Flk-1, is a receptor for PIGF, suggesting that the weak biological activities of PIGF are due to its use of only part of the available VEGF signaling. These mild characteristics of PIGF may be important for the appropriate development and maintenance of normal placental tissue.

Preeclampsia - An endothelial cell disorder plus 'something else'? (Reply)

Article

Jan 1990

Expression of Vascular Endothelial Growth Factor and Placenta Growth Factor in Human Placenta1

Article

Feb 1997

Piia Vuorela

Normal development and function of the placenta requires invasion of the maternal decidua by trophoblasts, followed by abundant and organized vascular growth. Little is known of the significance and function of the vascular endothelial growth factor (VEGF) family, which includes VEGF, VEGF-B, and VEGF-C, and of placenta growth factor (PIGF) in these processes. In this study we have analyzed the expression of VEGF and PIGF mRNAs and their protein products in placental tissue obtained from noncomplicated pregnancies. Expression of VEGF and PIGF mRNA was observed by in situ hybridization in the chorionic mesenchyme and villous trophoblasts, respectively. Immunostaining localized the VEGF and PIGF proteins in the vascular endothelium, which was defined by staining for von Willebrand factor and for the Tie receptor tyrosine kinase, an early endothelial cell marker. VEGF-B and VEGF-C mRNAs were strongly expressed in human placenta as evidenced by Northern blot analysis. These data imply that VEGF and PIGF are produced by different cells but that both target the endothelial cells of normal human term placenta.

Hypoxia Stimulates Cytokine Production by Villous Explants from the Human Placenta

Article

May 1997

Deborah Benyo

Microvascular Perturbations in Human Allografts: Analogies in Preeclamptic Placentae

Article

Apr 1992

The thromboresistance of endothelium is maintained as long as natural anticoagulant pathways are functionally present on endothelial plasma membranes. The principal anticoagulant pathways in human hearts and kidneys are thrombomodulin (TM) and heparan sulfate proteoglycan-antithrombin III (HSPG-ATIII). The downregulation of TM or the loss of ATIII is associated with fibrin deposition. This sequence of events occurs when stable allografts of hearts or kidneys become unstable or rejected. Human placentae do not contain the HSPG-ATIII natural anticoagulant pathway, but the TM system is uniformly represented on endothelium of normal chorionic villi. However, many villi in placentae from preeclamptic pregnancies contain thrombomodulin-negative endothelium, and these vessels contain fibrin thrombi. These thrombi compromise blood flow through the placental microcirculation and are associated with ischemic changes either with or without the presence of cellular infiltrates.

Preeclampsia: An endothelial cell disorder

Article

Dec 1989
AM J OBSTET GYNECOL

Despite intense study preeclampsia remains enigmatic and a major cause of maternal and fetal morbidity and mortality. Most investigative efforts have focused on the hypertensive component of this disorder with reduced attention given to other equally important characteristics. Increased sensitivity to pressor agents and activation of the coagulation cascade occur early in the course of preeclampsia, often antedating clinically recognizable disease. Inasmuch as endothelial cell injury reduces the synthesis of vasorelaxing agents, increases the production of vasoconstrictors, impairs synthesis of endogenous anticoagulants, and increases procoagulant production, these cells are likely to be implicated in the pathophysiology of preeclampsia. Indeed, evidence of endothelial cell injury is provided by the most characteristic morphologic lesion of preeclampsia, glomerular endotheliosis. Additional support for this hypothesis is derived from reports that indicate increased levels of circulating fibronectin (which can be released from injured endothelial cells) and increased factor VIII antigen present in the blood of preeclamptic women. More recently, direct evidence of activities that injure endothelial cells in vitro and increase the contractile sensitivity of isolated vessels has been presented. We propose that poorly perfused placental tissue releases a factor(s) into the systemic circulation that injuries endothelial cells. The changes initiated by endothelial cell injury set in motion a dysfunctional cascade of coagulation, vasoconstriction, and intravascular fluid redistribution that results in the clinical syndrome of preeclampsia.

An ultrastructural and ultrahistochemical study of the human placenta in maternal pre-eclampsia *

Article

Mar 1980
PLACENTA

At the electronoptical level the placental villi of the pre-eclamptic woman are characterized by focal syncytial necrosis, loss and distortion of microvilli, dilatation of syncytial rough endoplasmic reticulum, decreased syncytial pinocytotic activity, a reduced number of syncytial secretory droplets, cytotrophoblastic hyperplasia, degeneration of occasional cytotrophoblastic cells, thickening of the trophoblastic basement membrane and the presence of small fetal capillaries with bulbous endothelial cells. Ultrahistochemical studies show reduced alkaline phosphatase and dehydrogenase activity in the syncytiotrophoblast but an increased acid phosphatase activity. It is suggested that all the observed morphological abnormalities, with the exception of cytotrophoblast cell degeneration, are explicable solely on the basis of utero-placental ischaemia and that no other aetiological factor need be invoked: the cause of the cytotrophoblast cell degeneration is, however, unknown. The ultrastructural findings indicate that there is a decrease in the transfer and synthetic activity of the trophoblast and that cellular respiration is also probably depressed. Nevertheless, there is some evidence that changes of a compensatory nature, designed to limit the effects of the tissue damage, are brought into play.

Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity

Article

Nov 1995

Retinopathy of prematurity (ROP) is initiated by hyperoxia-induced obliteration of newly formed blood vessels in the retina of the premature newborn. We propose that vessel regression is a consequence of hyperoxia-induced withdrawal of a critical vascular survival factor. We show that regression of retinal capillaries in neonatal rats exposed to high oxygen, is preceded by a shut-off of vascular endothelial growth factor (VEGF) production by nearby neuroglial cells. Vessel regression occurs via selective apoptosis of endothelial cells. Intraocular injection of VEGF at the onset of experimental hyperoxia prevents apoptotic death of endothelial cells and rescues the retinal vasculature. These findings provide evidence for a specific angiogenic factor acting as a vascular survival factor in vivo. The system also provides a paradigm for vascular remodelling as an adaptive response to an increase in oxygen tension and suggests a novel approach to prevention of ROP.

Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14.

Article

May 1993
ONCOGENE

We have previously reported on the identification of a cDNA (placenta growth factor, PlGF) coding for a novel angiogenic factor expressed in placental tissue that is similar to vascular permeability factor/vascular endothelial growth factor (VPF/VEGF). Biochemical and functional characterization of PlGF derived from transfected COS-1 cells revealed that it is a glycosylated dimeric secreted protein able to stimulate endothelial cell growth in vitro. Here, we report the isolation and characterization of the PlGF gene located on chromosome 14. At least two different mRNAs are produced from this single-copy gene in different cell lines and tissues. Sequence comparison of the polypeptides encoded by the two different isolated cDNAs indicates that they are identical except for the insertion of a highly basic 21 amino acid stretch at the carboxyl end of the protein. RNA expression analysis of several tissues, tumors and cell lines indicates differential distribution of the two PlGF mRNAs. Finally, preliminary results indicate that the PIGF gene has been conserved in evolution, since the human PlGF cDNA hybridizes to sequences present in the genomic DNA of Drosophila, Xenopus, chicken and mouse.

Hypoxia alters early gestation human cytotrophoblast differentiation/invasion in vitro and models the placental defects that occur in preeclampsia

Article

Feb 1996

During normal human pregnancy a subpopulation of fetal cytotrophoblast stem cells differentiate and invade the uterus and its arterioles. In the pregnancy disease preeclampsia, cytotrophoblast differentiation is abnormal and invasion is shallow. Thus, the placenta is relatively hypoxic. We investigated whether lowering oxygen tension affects cytotrophoblast differentiation and invasion. Previously we showed that when early gestation cytotrophoblast stem cells are cultured under standard conditions (20% O2) they differentiate/invade, replicating many aspects of the in vivo process. Specifically, the cells proliferate at a low rate and rapidly invade extracellular matrix (ECM) substrates, a phenomenon that requires switching their repertoire of integrin cell-ECM receptors, which are stage-specific antigens that mark specific transitions in the differentiation process. In this study we found that lowering oxygen tension to 2% did not change many of the cells' basic processes. However, there was a marked increase in their incorporation of [3H]thymidine and 5-bromo-2'-deoxyuridine (BrdU). Moreover, they failed to invade ECM substrates, due at least in part to their inability to completely switch their integrin repertoire. These changes mimic many of the alterations in cytotrophoblast differentiation/invasion that occur in preeclampsia, suggesting that oxygen tension plays an important role in regulating these processes in vivo.

Hypoxia impairs cell fusion and differentiation process in human cytotrophoblast, in vitro

Article

Aug 1996

During human pregnancy, the trophoblast develops from differentiation of cytotrophoblast cells into an endocrine active syncytiotrophoblast. In culture, isolated mononuclear cytotrophoblasts aggregate and then fuse to form a syncytium, reproducing the in vivo process. In this study, we examined the effect of low oxygen tension (approximately 9%, hypoxia) compared to standard conditions (approximately 19% oxygen, normoxia) on these cellular events. Under hypoxia, syncytial formation was less frequently observed, cell staining and electron microscopy revealed that cytotrophoblasts remain aggregated, with a positive proliferative cell nuclear antigen (PCNA) immunostaining. Desmoplakin and E-cadherin, both known to disappear with cytotrophoblast fusion, showed persistent expression in hypoxic cells after 3 days of culture. In contrast, the expression of actin and ezrin, two cytoskeletal proteins, was unchanged. hCG secretion and hPL expression were both decreased in hypoxic cells, reflecting a reduced syncytial formation. Thus, on day 3, the mean values for hCG secretion were 1,100 +/- 155 and 289 +/- 26 mlU/mL in normoxic and hypoxic conditions, respectively. The reduced cell fusion process as well as hCG secretion and hPL expression under hypoxia were reversed by reoxygenation of the cells. We conclude that under hypoxia, the formation of functional syncytiotrophoblast is impaired due to a defect in the cytotrophoblast fusion process. This may explain the observation of a higher number of cytotrophoblast cells and a reduced syncytial layer in placentas of some pathological pregnancies.

The Effect of hypoxia on term trophoblast: Hormone synthesis and release

Article

May 1996
PLACENTA

Isolated trophoblast in culture remained viable when exposed to severe hypoxia (Po2 12-14 mmHg) for at least 72 h as indicated by trypan blue exclusion and the synthesis and secretion of metabolically labelled proteins. However, release of hCG, hPL, progesterone and estradiol was reduced to < 10 per cent when compared to trophoblast in normoxia (Po2 120-130 mmHg). hCG mRNA was also reduced demonstrating interruption of synthesis at transcription. Acute exposure to hypoxia (2 h) suppressed progesterone release but not hCG, whereas inhibitors of oxidative phosphorylation suppressed hCG release but not progesterone. hCG release increases progressively during culture in normoxia, peaking at 72 h. Exposure of trophoblast to hypoxia for 48 h after 24, 48 and 72 h in normoxia interrupted this progression but did not suppress hCG release. Progesterone release, in contrast, was reduced by hypoxia. Exogenous dibutyryl cAMP increased hCG and progesterone release by normoxic trophoblast but not by hypoxic cells. Trophoblast returned to normoxia after 24 h in hypoxia increased hCG and progesterone release, suggesting early recovery. Conservation of oxygen and ATP by reducing hormone synthesis may contribute to survival of trophoblast in hypoxia.

Identification of a Natural Soluble Form of the Vascular Endothelial Growth Factor Receptor, FLT-1, and Its Heterodimerization with KDR

Article

Oct 1996

A soluble form of the vascular endothelial growth factor (VEGF) receptor FLT-1 was identified in conditioned culture medium of human umbilical vein endothelial cells. The endogenous soluble FLT-1 (sFLT-1) receptor is chromatographically and immunologically similar to recombinant human sFLT-1 and binds [125I]VEGF with a comparable high affinity. Human sFLT-1 is shown to form a VEGF-stabilized complex with the extracellular domain of KDR in vitro, suggesting that not only full-length receptors are capable of forming ligand-induced heterodimeric complexes but also sFLT-1 can form a dominant negative complex with the mitogenically competent full-length KDR receptor.

Localisation of Placenta Growth Factor (PlGF) in Human Term Placenta

Article

Feb 1996

Placenta growth factor (PlGF) is a growth factor which belongs to the vascular endothelial growth factor (VEGF) family and is known to bind to the fms-like tyrosine kinase receptor (flt-1). Using Western blot analysis a 50 kDa band was identified in placental protein extract which corresponded to PlGF homodimer. Immunoreactive PlGF was localised to the vasculosyncytial membrane and in the media of large blood vessels of the placental villi, while staining within the mesenchyme was weak and diffuse. There was moderate staining for PlGF in discrete cells in the chorion and no staining in the epithelial layer of the amnion. The maternal decidual cells showed strong staining for PlGF immunoreactive protein. PlGF mRNA was predominantly expressed by the vasculosyncytial membrane of villous trophoblast, whilst there was no apparent expression of PlGF mRNA within the villous mesenchyme. These results suggest that PlGF may be an important paracrine factor for vascular endothelial cells in placental angiogenesis and an autocrine mediator of trophoblast function.

Intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery is associated with maldevelopment of the placental terminal villous tree

Article

Dec 1996
AM J OBSTET GYNECOL

Our purpose was to evaluate the structure of placental terminal villi and their capillaries in pregnancies complicated by intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery. Glutaraldehyde-perfusion-fixed villous tissue and a plastic cast of the vessels in at least two cotyledons were prepared from 10 cases with intrauterine growth restriction and 9 gestational age-matched control placentas. The structure and dimensions of 20 terminal capillary loops per cast were determined by scanning electron microscopic examination, and their appearances were correlated with the peripheral villi of the perfusion-fixed villous tissue. Capillary loops in the growth-restricted cases were sparse in number and significantly longer than in the control cases (218 microns [72] vs 137 microns [30], mean and SD, p < 0.05). They exhibited fewer branches (4.0 [1.9] per loop vs 6.1 [2.2], p < 0.05) and a majority of loops were uncoiled (79% vs 18%, p < 0.05). The villous tissues from the growth-restricted cases demonstrated elongated villi, consistent with the cast findings. The trophoblast surface was wrinkled and in some areas covered by fibrin plaques. The terminal villous compartment of the placenta appears to be maldeveloped in preterm intrauterine growth restriction pregnancies where absent end-diastolic flow velocity is demonstrated in the umbilical artery before delivery. These findings are consistent with an increase in fetoplacental vascular impedance at the capillary level and may account for the impaired gas and nutrient transfer in this disorder.

Hypertension in pregnancy: Current Concepts of Preeclampsia

Article

Feb 1997

Hypertensive disorders (gestational hypertension, preeclampsia, chronic hypertension, superimposed preeclampsia) are the most common medical complications of pregnancy and constitute a major cause of maternal and perinatal morbidity and mortality. Prediction of those women destined to develop preeclampsia remains elusive. The benefits of calcium supplementation for prevention of preeclampsia are encouraging; however, the definitive study is not yet complete. Aspirin therapy for high-risk has not been helpful; results of therapy for high-risk women are pending. More experience is being gained with antihypertensive therapy and expectant management in severe preeclampsia. Conservative management of severe preeclampsia, when performed in a tertiary care center, may benefit a select group of women and their fetuses.

Maternal circulation in the first-trimester human placenta—Myth or reality?

Article

Apr 1997
AM J OBSTET GYNECOL

The classic theory of development of the uteroplacental and intervillous circulation determined that maternal blood enters the intervillous space in high-pressure streams from the early first trimester. This theory has recently been challenged and our hypothesis to be presented is that the intervillous circulation is not fully established until the end of the first trimester. Ex vivo studies of hysterectomy specimens have demonstrated that trophoblastic plugs obstruct blood flow into the intervillous space in early pregnancy and only at 12 to 13 weeks do these plugs become loose and allow for continuous maternal blood flow into the intervillous space. This concept is supported by many other experimental findings. In complicated early pregnancies the uteroplacental circulation demonstrates flow characteristics that are strikingly different from those of normal early pregnancies. In abnormal pregnancies increased flow within the intervillous space is demonstrated by color Doppler imaging. Our hypothesis supports other studies that have shown that the embryo favors an environment low in oxygen during early development and that oxygen levels in placental tissue are low in the early first trimester. The classic drawing of placental circulations is based on second- and third-trimester studies, and its applicability to the early first trimester should be revisited because we will show that new data support the hypothesis that the development of the early intervillous circulation is a progressive phenomenon.

The effect of hypoxia on human trophoblast in culture: Morphology, glucose transport and metabolism

Article

Mar 1997
PLACENTA

The response to hypoxia of trophoblast isolated from term placenta and maintained in culture was studied. Trophoblast exposed to normoxic (PO2 120-130 mmHg) or hypoxic (PO2 12-14 mmHg) conditions were examined by electron microscopy. After 48 h, the cytoplasm of the hypoxic cells was more electron-dense with increased numbers of mitochondria, lysosomes and vacuoles. Compared to normoxic cells, the surface microvilli of the hypoxic cells were sparse, short and unevenly distributed. [3H]thymidine incorporation by both hypoxic and normoxic trophoblast fell rapidly and equivalently after 2 days in culture. The percentage of cells with the proliferation-associated nuclear antigen, Ki 67, also decreased, but remained higher in hypoxic cells suggesting that hypoxia retarded completion of the cell cycle (normoxia, 10.80 +/- 2.51 s.e.; hypoxia, 19.87 +/- 2.73, P < 0.01). Glucose consumption was elevated in hypoxia (3.73 +/- 1.07 s.e. mumol/10(6) cells/24 h) as compared to normoxia (1.46 +/- 0.83, P = 0.01). Although lactate production was consistently higher in hypoxia, the difference was not statistically significant (hypoxia 5.38 +/- 1.54 mumol/10(6) cells/24 h versus normoxia, 1.52 +/- 0.29, P = 0.07). After 48 h, uptake of [3H]2-deoxglucose ([3H]2DG) by hypoxic cells was reduced to 12 per cent +/- 4.3 s.e. of that in normoxic cells; return to normoxia resulted in recovery within 10 min. Lineweaver-Burk plots of [3H]2DG uptake indicated high affinity (KM 2.2 +/- 0.4 x 10(-4) M) and low affinity transporters (KM 4.5 +/- 1.6 x 10(-3) M). Northern blot analysis identified mRNA for GLUT1 and GLUT3. In hypoxia, steady-state GLUT1 and GLUT3 mRNA were approximately three- and 10-fold higher than in normoxia respectively. Inhibitors of oxidative metabolism of glucose increased the uptake of [3H]2DG within 2 h, whereas hypoxia reduced uptake. Hence, trophoblast in culture survives in extreme hypoxia, but manifests striking changes in morphology and in glucose metabolism and transport. Completion of cell cycle appears to be retarded.

Placenta growth factor-1 is chemotactic, mitogenic, and angiogenic

Article

May 1997

The placental-derived growth factor (PIGF) is a dimeric glycoprotein showing a high degree of sequence similarity to the vascular endothelial growth factor. Alternative splicing of the PIGF primary transcript gives rise to two forms, named PIGF-1 and PIGF-2, which differ only in the insertion of a highly basic 21-amino acid stretch at the carboxyl end. The presence of the PIGF mRNA in thyroid, placenta, lung, and goiter has indicated the tissues where this factor functions. However, the role of PIGF in vascular development has not yet been clearly established. In the present study, we described the purification of PIGF-1 from overexpressing eukaryotic cells and then measured the angiogenic activity of the purified PIGF-1 in vivo in the rabbit cornea and the chick chorioallantoic membrane assays. In both in vivo assays, PIGF-1 induced a strong neovascularization process that was blocked by affinity-purified anti-PIGF-1 antibody. In the avascular cornea, PIGF-1 induced angiogenesis in a dose-dependent manner and seemed to be at least as effective (if not more effective) than vascular endothelial growth factor and basic fibroblast growth factor under the same conditions and at the same concentration. PIGF-1 was shown to induce cell growth and migration of endothelial cells from bovine coronary postcapillary venules and from human umbilical veins. In these two in vitro assays, PIGF-1 seemed to have a comparable effect to that of vascular endothelial growth factor and basic fibroblast growth factor on the cultured microvascular endothelium (eg, capillary venule endothelial cells). In summary, this is the first study to demonstrate that PIGF-1 can induce angiogenesis in vivo and stimulate the migration and proliferation of endothelial cells in vitro.

Placental Cytokines and the Pathogenesis of Preeclampsia

Article

Apr 1997

The authors explore the hypothesis that tumor necrosis factor-alpha (TNF-alpha) and possibly other inflammatory cytokines are overproduced by the placenta in response to local ischemia/hypoxia contributing to increased plasma levels, and subsequent endothelial activation and dysfunction in the pregnancy disorder, preeclampsia. It is widely held that inadequate trophoblast invasion and physiologic remodeling of spiral arteries initiate placental ischemia/hypoxia in preeclampsia. Furthermore, focal areas of placental hypoxia have been implicated in the production of "toxic" factor(s) by the placenta, which circulate and cause maternal disease. Placental trophoblast cells and fetoplacental macrophages normally produce TNF-alpha and interleukin-1 (IL-1), which are capable of producing endothelial cell activation and dysfunction. Hypoxia has recently been reported to increase TNF-alpha and IL-1 production by term villous explants from the human placenta. Placental cells also express erythropoietin (EPO), which is the prototype molecule for transcriptional regulation by hypoxia in mammals. Interestingly, TNF-alpha and IL-1 have DNA sequence homologous or nearly homologous to the hypoxia-responsive enhancer element of the EPO gene, thus providing a potential, but as of yet, untested molecular link between placental hypoxia and stimulation of cytokine production. Inflammatory cytokines overproduced by the placenta in response to hypoxia may then lead to increased plasma levels and endothelial activation and dysfunction in preeclampsia. The purpose of this short review is to critically evaluate the hypothesis that placental cytokines contribute to the pathogenesis of preeclampsia. Of note, the etiology of the disease presumably related to deficient trophoblast invasion is beyond the scope of this work.

Review: Immunobiology of Preeclampsia

Article

Feb 1997

Robert N. Taylor

Preeclampsia has been recognized clinically since the time of Hippocrates: however its etiology and pathophysiology remain enigmatic. This pregnancy-specific syndrome typically presents in late pregnancy as hypertension, edema, and proteinuria. Investigations over the past 15 years have revealed that preeclampsia is associated with abnormal placentation, reduced placental perfusion, endothelial cell dysfunction, and systemic vasospasm. Since it occurs more commonly in primigravidae and in women with underlying collagen-vascular diseases, an immunological component has long been suspected. Increased prevalence in high-order and molar pregnancies and those associated with increased placental mass suggests that trophoblastic volume and fetal antigen load are correlated with the syndrome. Epidemiological reports indicate that the prevalence of preeclampsia is decreased in women who received heterologous blood transfusions, practiced oral sex, or when a long period of cohabitation preceded an established pregnancy. Conversely, the use of condoms as a primary mode of contraception is associated with a higher risk of preeclampsia. These studies suggest that prior exposure to foreign or paternal antigens imparts a protection against the likelihood of developing preeclampsia. Clinical evidence of cellular and humoral immune dysfunction is associated with the syndrome. Fibrin and complement deposition and "foam" cells in atherosis lesions resemble the histopathology of renal allograft rejection. Relative T-cell, natural killer cell, and neutrophil activation have been reported in preeclampsia and circulating cytokines and antiphospholipid antibodies are more prevalent in preeclampsia than in normal pregnant women. These abnormalities are consistent with the systemic endothelial cell dysfunction that has been postulated as a pathophysiological feature of preeclampsia. While such associations do not prove causality, they suggest testable hypotheses for continued basic and clinical investigation of this major complication of human pregnancy.

Vascular endothelial growth factor, placenta growth factor and their receptors in isolated human trophoblast

Article

Dec 1997
PLACENTA

The expression of the angiogenic growth factors, vascular endothelial cell growth factor (VEGF) and placenta growth factor (PIGF) was demonstrated in isolated human term cytotrophoblast and in vitro differentiated syncytiotrophoblast. RNase protection assays demonstrated VEGF expression in both cytotrophoblast and syncytiotrophoblast while prominent PIGF expression was detected in both types of trophoblast by Northern blot analyses. VEGF expression increased approximately eightfold in trophoblast cultured under hypoxic conditions (1 per cent O2) yet PIGF expression decreased 73 +/- 5.5 per cent in the same trophoblast. These results suggest distinct regulatory mechanisms govern expression of VEGF and PIGF in trophoblast. Characterization of the VEGF/PIGF receptors, KDR and flt-1, revealed the presence of flt-1 mRNA in isolated cytotrophoblast and in vitro differentiated syncytiotrophoblast. KDR was not detected in the isolated trophoblast. Exogenous rhVEGF induced c-Jun N-terminal kinase (JNK) activity in the normal trophoblast indicating that the flt-1 receptors on trophoblast are functional. Trophoblast-derived VEGF/PIGF could act in a paracrine fashion to promote uterine angiogenesis and vascular permeability within the placental bed. In addition, presence of function flt-1 on normal trophoblast suggests that VEGF/PIGF functions in an autocrine manner to perform an as yet undefined role in trophoblast invasion, differentiation, and/or metabolic activity during placentation.

Cushing's disease in childhood

Article

Sep 1996
TRENDS ENDOCRIN MET

Cushing's disease is rare in childhood. There is an equal sex incidence, and it accounts for approximately 75% of pediatric causes of Cushing's syndrome. Predominant features are weight gain, growth failure, virilization, and headache. Following confirmation of the presence of inappropriate hypercortisolemia, the accurate differential diagnosis to establish the pituitary as the source of excessive ACTH secretion involves demonstration of > 50% suppression of circulating cortisol during high-dose dexamathasone administration and exaggeration of the cortisol response to corticotropin-releasing hormone (CRH). Imaging of the pituitary reveals a microadenoma in only a minority of cases, but inferior petrosal sinus sampling for ACTH can be of value in confirming the pituitary location of the tumor and possibly its lateralization. Primary therapy is transsphenoidal surgery, which can be supported by direct pituitary irradiation if hypercortisolemia persists. In experienced hands, the therapeutic outcome is good.

National High Blood Pressure Education Program Working Group report on high blood pressure in pregnancy

Jan 1990
1691

Anonymous

Anonymous. National High Blood Pressure Education Program Working Group report on high blood pressure in pregnancy. Am J Obstet Gynecol 1990;163:1691-712.

Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor

Jan 1991
9267

Maglione

Preeclampsia is associated with reduced serum levels of placenta growth factor

Abstract

No full-text available

Recommended publications

Changes in Circulating Level of Angiogenic Factors from the First to Second Trimester as Predictors...