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Histomorphological view of chorionic villi in a term placenta derived form a normal woman. The placental tissue was stained with hematoxylin and eosin (abbreviations in this and all other figures, other than Fig. 12: asterisks blood vessels, s syncytiotrophoblast layer, m mesenchyme, is intervillous space)
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This study explores the molecular composition of the tight junction (TJ) in human term placenta from normal women and from patients with preeclampsia, a hypertensive disorder of pregnancy. Maternal endothelial dysfunction is a critical characteristic of preeclampsia; hence, we have analyzed its impact on placental vessels. The study concentrates on...
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... order to facilitate the interpretation of the subsequent immunofluorescent images, we present a histomorpholog- ical view of chorionic villi in a term placenta derived from a normal woman (Fig. 1). Numerous blood vessels and the syncytiotrophoblast layer surrounded by the intervillous space can be seen in the chorionic ...
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... 16 at the plasma membrane, we incubated placental tissue with antibodies against claudin 16 and the apical membrane glycoprotein GP135 or the basolateral membrane protein Na + K + - ATPase and, in both cases, stained the cell nuclei with propidium iodide. Claudin 16 immunoreactivity colocal- ized with that of GP135 ( Fig. 9) and Na + K + -ATPase (Fig. 10) at the plasma membrane. Whereas in epithelial cells, the distribution of these proteins was markedly polarized to either the apical or the basolateral plasma membrane surfaces, they appeared to display a less-well- defined pattern of polarization in the syncytiotrophoblast layer. This was further confirmed when the placental tissue was ...
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... the distribution of these proteins was markedly polarized to either the apical or the basolateral plasma membrane surfaces, they appeared to display a less-well- defined pattern of polarization in the syncytiotrophoblast layer. This was further confirmed when the placental tissue was co-stained with antibodies against GP135 and Na + K + - ATPase (Fig. 11a,b). The confocal xz sections of normal tissue (Fig. 11b) showed in more detail that, although the Na + K + -ATPase was concentrated at the lateral membranes of the syncytiotrophoblast layer, significant immunoreac- tivity could also be detected at the apical membrane. In a similar fashion, GP135 was clearly detectable at the apical ...
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... to either the apical or the basolateral plasma membrane surfaces, they appeared to display a less-well- defined pattern of polarization in the syncytiotrophoblast layer. This was further confirmed when the placental tissue was co-stained with antibodies against GP135 and Na + K + - ATPase (Fig. 11a,b). The confocal xz sections of normal tissue (Fig. 11b) showed in more detail that, although the Na + K + -ATPase was concentrated at the lateral membranes of the syncytiotrophoblast layer, significant immunoreac- tivity could also be detected at the apical membrane. In a similar fashion, GP135 was clearly detectable at the apical surface (arrowhead) but still displayed some positive ...
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... xz sections of the preeclamptic placentae displayed a more diffuse pattern of staining (data not shown). 16 is absent from the placental vessels, whereas it strongly immuno- reacts with the plasma mem- brane of the syncytiotrophoblast layer. a No claudin 16 is de- tected in the placental endothelia identified by its positive PECAM-1 immunoreactivity. ...
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... densitometric analysis of all the samples. Each point on the graph corre- sponds to an individual pa- tient (means±SE) Electron-microscopic observations Electron microscopy revealed that, in both normal and preeclamptic placentae, the extracellular marker ruthenium red stained the microvilli of the apical surface of the syncytiotrophoblast layer (Fig. 12, arrows). The penetra- tion of the marker was prevented at the uppermost portion of the lateral membrane, the location of the TJs (arrow- heads). The paracellular pathway traversed the syncytio- trophoblast layer connecting the maternal intervillous space (Fig. 12, asterisk) to the fetal extracellular compart- ment found below the ...
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... red stained the microvilli of the apical surface of the syncytiotrophoblast layer (Fig. 12, arrows). The penetra- tion of the marker was prevented at the uppermost portion of the lateral membrane, the location of the TJs (arrow- heads). The paracellular pathway traversed the syncytio- trophoblast layer connecting the maternal intervillous space (Fig. 12, asterisk) to the fetal extracellular compart- ment found below the syncytiotrophoblast layer (Fig. 12, double asterisks). In this tissue, the paracellular pathway exhibited both a winding (Fig. 12a) and a linear-like ( Fig. 12b) pattern; however, the former was more frequently observed in both the normal and the preeclamp- tic ...
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... The penetra- tion of the marker was prevented at the uppermost portion of the lateral membrane, the location of the TJs (arrow- heads). The paracellular pathway traversed the syncytio- trophoblast layer connecting the maternal intervillous space (Fig. 12, asterisk) to the fetal extracellular compart- ment found below the syncytiotrophoblast layer (Fig. 12, double asterisks). In this tissue, the paracellular pathway exhibited both a winding (Fig. 12a) and a linear-like ( Fig. 12b) pattern; however, the former was more frequently observed in both the normal and the preeclamp- tic ...
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... the location of the TJs (arrow- heads). The paracellular pathway traversed the syncytio- trophoblast layer connecting the maternal intervillous space (Fig. 12, asterisk) to the fetal extracellular compart- ment found below the syncytiotrophoblast layer (Fig. 12, double asterisks). In this tissue, the paracellular pathway exhibited both a winding (Fig. 12a) and a linear-like ( Fig. 12b) pattern; however, the former was more frequently observed in both the normal and the preeclamp- tic ...
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... heads). The paracellular pathway traversed the syncytio- trophoblast layer connecting the maternal intervillous space (Fig. 12, asterisk) to the fetal extracellular compart- ment found below the syncytiotrophoblast layer (Fig. 12, double asterisks). In this tissue, the paracellular pathway exhibited both a winding (Fig. 12a) and a linear-like ( Fig. 12b) pattern; however, the former was more frequently observed in both the normal and the preeclamp- tic ...
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... is affected during preeclampsia comes from the observation that, in this pathological state, not only the maternal serum, but also that derived from the umbilical cord exhibit a lower amount of the potent vasodilators, calcitonin gene- related and parathyroid hormone-related peptides, than in normotensive pregnant women (Halhali et al. 2001). Fig. 10 Claudin 16 colocalizes with the plasma membrane pro- tein Na + K + ATPase in the syncy- tiotrophoblast of the placentae from normal and preeclamptic women. The placental tissue was treated with propidium iodide (PI) for identification of the nu- clei and with antibodies against claudin 16 and Na + K + ...
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... are compatible with the formation of a cation selective channel. Recently, another human disease, viz. idiopathic hypercalciuria, which is characterized by abnor- mal renal loss, has been shown to result from mutations in claudin 16 that block its localization at the TJ and instead lead to its accumulation at the lysosome ( Muller et al. 2003 Fig. 11 Na + K + ATPase and GP135 display a mildly polarized pattern in the plasma membrane of the syncytiotrophoblast layer. The placental tissue was treated with propidium iodide (PI) for identifi- cation of the nuclei and with antibodies against Na + K + ATPase and GP135. a Confocal xy sections. b Confocal xz sections. GP135 was readily ...
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... a speculative perspective, the conspicuous expres- sion of claudin 16 at the lateral plasma membrane of the Fig. 12 Paracellular pathway of the syncytiotrophoblast layer connects the fetal interstitium with the maternal blood space and blocks the passage of ruthe- nium red at the TJ region (as- terisks maternal blood space, double asterisks fetal extracellu- lar compartment located under the syncytiotrophoblast layer). Placentae from both normal (a) ...
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Citations
... Silencing SEMP1 notably suppressed cell growth, migration, and invasion in human gastric adenocarcinoma cells [15]. Significantly, decreased SEMP1 expression was observed in the placental endothelial vessels of PE patients [17], but the mechanism of SEMP1 in PE had not been well studied. ...
... Yao and co-authors suggested that ephrin-A2 promoted cell migration and invasion in vitro and facilitated tumor growth in vivo by downregulating the expression of SEMP1 in prostate cancer cells [31]. Remarkably, it had been reported that the SEMP1 gene was downregulated in the placental endothelial vessels of PE patients [17]. In line with these results, we found that SEMP1 presented a decrease in the spiral artery of PE rats. ...
Disturbance of extravillous trophoblast infiltration is associated with preeclampsia (PE), a severe condition of pregnancy characterized by hypertension and proteinuria. Senescence-associated epithelial membrane protein 1 (SEMP1), an integral membrane protein, is a vital component of tight junction strands in epithelial or endothelial cells, with no clear function reported in PE. Gene Expression Omnibus (GEO) datasets showed that SEMP1 expression was downregulated in the placental tissues of PE patients, which was confirmed by assessing SEMP1 levels in placental samples collected in our hospital. Furthermore, less SEMP1 was detected in cytokeratin 7 positive trophoblast cells in the spiral arteries of rat placentas post L-arginine methyl ester hydrochloride (L-NAME) treatment. Trophoblast cells acquired robust ability of proliferation, migration, and invasion when SEMP1 was overexpressed. Such capability was weakened in SEMP1-silenced cells. Trophoblast cells overexpressing SEMP1 secreted more vascular endothelial growth factor A (VEGFA), which facilitated the tube formation of human umbilical vein endothelial cells. Blockade of PI3K/AKT signaling transduction with LY294002 dampened the effects of SEMP1 on trophoblast cells. Collectively, we firstly indicated that SEMP1 inhibition is a potential driver for PE, which may be associated with the deactivation of the PI3K/AKT pathway.
Graphical Abstract
SEMP1 was involved in PE progression by regulating cell growth, migration, invasion, and tube formation via PI3K/AKT signaling pathway in trophoblast cells and endothelial cells.
... Furthermore, the researchers evaluated the HIF1α expression in preeclamptic and healthy placentae, and noticed a significant increase of HIF1α expression in preeclamptic patients, so they concluded that hypoxia may underlie the etiology of preeclampsia through cellular signaling pathways in which HIF1α participates [72]. Although Lievano et al. observed no differences in OCLN and zo-1 placental immunostaining in preeclampsia, the expression of CLN1, CLN3, and CLN5 decreased, which may suggest the TJ unsealing, possibly as a result of decreased perfusion [73]. Because of the similar etiology between preeclampsia and FGR, related to hypoxia and placental insufficiency, searching for the changed placental TJ protein expression seems to be justified. ...
The aim of the study was to determine whether early-onset and late-onset fetal growth restriction (FGR) differentially affects the blood–brain barrier integrity. Furthermore, the purpose of the study was to investigate the relationship between the blood–brain barrier breakdown and neurological disorders in FGR newborns. To evaluate the serum tight junction (TJ) proteins and the placental TJ proteins expression, an ELISA method was used. A significant difference in serum OCLN concentrations was noticed in pregnancies complicated by the early-onset FGR, in relation to the intraventricular hemorrhage (IVH) occurrence in newborns. No significant differences in concentrations of the NR1 subunit of the N-methyl-d-aspartate receptor (NR1), nucleoside diphosphate kinase A (NME1), S100 calcium-binding protein B (S100B), occludin (OCLN), claudin-5 (CLN5), zonula occludens-1 (zo-1), the CLN5/zo-1 ratio, and the placental expression of OCLN, CLN5, claudin-4 (CLN4), zo-1 were noticed between groups. The early-onset FGR was associated with a higher release of NME1 into the maternal circulation in relation to the brain-sparing effect and premature delivery. Additionally, in late-onset FGR, the higher release of the S100B into the maternal serum in regard to fetal distress was observed. Furthermore, there was a higher release of zo-1 into the maternal circulation in relation to newborns’ moderate acidosis in late-onset FGR. Blood–brain barrier disintegration is not dependent on pregnancy advancement at the time of FGR diagnosis. NME1 may serve as a biomarker useful in the prediction of fetal circulatory centralization and extremely low birth weight in pregnancies complicated by the early-onset FGR. Moreover, the serum zo-1 concentration may have prognostic value for moderate neonatal acidosis in late-onset FGR pregnancies.
... Our study did not observe any difference in OCLN expression, which is in line with some previous research on pre-eclampsia and laboratory-induced hypoxia [67,68]. Contrary to this, Lim et al. and Wang et al. reported a decrease in OCLN expression at the protein level, although there were no changes in mRNA expression in patients diagnosed with pre-eclampsia compared to physiological pregnancy [45,69]. ...
... Moreover, pre-eclampsia coexisted with a disorganized pattern of TJ proteins [69]. Similar to our study, Lim et al. and Liévano et al. did not observe changes in zo-1 expression [45,67], whereas Zhang et al. noticed a decrease in zo-1 and CLN4 expression, as well as an increase in CLN8 expression [68]. Contrary to the increase in CLN5 expression observed in the present study, Liévano et al. found a decrease in CLN5, CLN1, and CLN3 expression [67]. ...
... Similar to our study, Lim et al. and Liévano et al. did not observe changes in zo-1 expression [45,67], whereas Zhang et al. noticed a decrease in zo-1 and CLN4 expression, as well as an increase in CLN8 expression [68]. Contrary to the increase in CLN5 expression observed in the present study, Liévano et al. found a decrease in CLN5, CLN1, and CLN3 expression [67]. This may suggest the existence of further pathways which control the placental claudin expression and distinct mechanisms of "up-" and "down-" regulation of TJ proteins in response to the conditions in utero. ...
This study evaluated the damage to the endothelial tight junctions (TJs) in pregnancies complicated by fetal growth restriction (FGR) and investigated whether FGR is related to blood–brain barrier disintegration and, subsequently, to the appearance of proteins indicative of neuronal injury in maternal blood. The studied group included 90 pregnant women diagnosed with FGR. The control group consisted of 70 women with an uncomplicated pregnancy. The biochemical measurements included serum neuronal proteins (subunit of the N-methyl-D-aspartate receptor—NR1, nucleoside diphosphate kinase A—NME1, and S100 calcium-binding protein B—S100B), serum TJ proteins (occludin—OCLN, claudin-5—CLN5, zonula occludens—zo-1, and OCLN/zo-1 and CLN5/zo-1 ratios), and placental expression of TJ proteins (OCLN, claudin-4 CLN4, CLN5, zo-1). The significantly higher serum S100B and CLN5 levels and serum CLN5/zo-1 ratio were observed in FGR compared to healthy pregnancies. Moreover, FGR was characterized by increased placental CLN5 expression. Both serum NME1 levels and placental CLN4 expression in FGR pregnancies were significantly related to the incidence of neurological disorders in newborns. Mothers of FGR neonates who developed neurological complications and intraventricular hemorrhage (IVH) had statistically higher NME1 concentrations during pregnancy and significantly lower placental CLN4 expression than mothers of FGR neonates without neurological abnormalities. The serum NME1 levels and placental CLN4 expression were predictive markers of IVH in the FGR group. The blood–brain barrier is destabilized in pregnancies complicated by FGR. Neurological disorders, including IVH, are associated with higher serum concentrations of NME1 and the decreased placental expression of CLN4. The serum NME1 levels and placental CLN4 expression may serve as biomarkers, helpful in predicting IVH in FGR. It may allow for more precise monitoring and influence decision-making on the optimal delivery time to avoid developing neurological complications.
... Contrary to our findings, Lievano et al. reported a decreased amount of CLN5 in preeclamptic placentae, but similar to us, the researchers observed no differences in the zo-1 immunostaining. That suggests leakier TJs in the endothelium of human placentae, possibly as a result of a decreased perfusion [79]. Itoh et al. detected the zo-1 protein in all human placental endothelial junctions, regardless of the pregnancy advancement, and the location in the vascular tree. ...
The endothelial cells of the blood-brain barrier adhere closely, which is provided by tight junctions (TJs). The aim of the study was to assess the damage to the endothelial TJs in pregnancy, complicated by fetal growth restriction (FGR) and circulatory centralization (brain-sparing effect, BS). The serum concentrations of NR1 subunit of the N-methyl-D-aspartate receptor (NR1), nucleoside diphosphate kinase A (NME1), S100 calcium-binding protein B (S100B), occludin (OCLN), claudin-5 (CLN5), and zonula occludens protein – 1 (zo-1), and the placental expressions of OCLN, claudin-4 (CLN4), CLN5, and zo-1 were assessed with ELISA. The significantly higher serum NME1 concentrations and the serum CLN5/zo-1 index were observed in FGR pregnancy with BS, as compared to the FGR group without BS. The FGR newborns with BS were about 20 times more likely to develop an intraventricular hemorrhage (IVH) than the FGR infants without BS. The cerebroplacental ratio (CPR) allowed to predict the IVH in growth-restricted fetuses. The significantly lower placental CLN4 expression was observed in the FGR group with BS and who postnatally developed an IVH, as compared to the growth-restricted infants with BS without IVH signs. Pregnancy complicated by FGR and BS is associated with the destabilization of the fetal blood-brain barrier. The IVH in newborns is reflected in the inhibition of the placental CLN4 expression, which may be a useful marker in the prediction of an IVH among growth-restricted fetuses.
... Ce sont des protéines transmembranaires exprimées dans les cellules endothéliales au niveau des jonctions qui maintiennent l'adhérence cellulaire. Par ailleurs, la claudine 1 et PECAM sont colocalisées dans de nombreux tissus (Liévano et al., 2006;Pfeiffer et al., 2011). ...
Les tumeurs mammaires triple-négatives (TNBC) représentent 20 % des cancers du sein et leur traitement constitue un enjeu majeur en cancérologie puisque peu de thérapies ciblées efficaces sont actuellement disponible pour les patients. Parmi les TNBC, 77% n'expriment pas la claudine 1 (une protéine des jonctions serrées) et sont appelés tumeurs « claudin-1-low ». Ces dernières présentent un risque accru de récidives, d'importantes capacités métastatiques ainsi qu'une forte résistance à la chimiothérapie. Bien que le rôle de la claudine 1 dans le cancer du sein ne soit pas clairement défini, plusieurs équipes suggèrent qu'elle pourrait être un suppresseur de tumeur. Dans ce contexte, mon laboratoire a pu montrer que son expression induisait l'apoptose de deux lignées cellulaires TNBC « claudin-1-low » : les MDA- MB-231 et les Hs578T. Les travaux établis au cours ma thèse ont démontré qu'au sein des TNBC, les cellules HCC1806 exprimant la claudine 1 présentent une plus forte sensibilité que les cellules MDA-MB-231 et Hs578T à trois agents de chimiothérapie couramment utilisés en clinique dans le traitement des tumeurs mammaires : le 5-FU, le paclitaxel et la doxorubicine. Les résultats obtenus soulignent également l'implication de la claudine 1 dans cette sensibilité, et que son expression sensibilise les lignées TNBC « claudin-1-low » aux agents de chimiothérapie. Dans le but de comprendre son implication dans ce processus, la recherche de ses partenaires protéiques, ainsi que l'identification des régulateurs clés de son expression ont été initiés. L'ensemble des travaux effectués au cours de cette thèse pourrait permettre d'établir la claudine 1 comme marqueur pronostic de réponse à la chimiothérapie. A plus long terme, ces travaux pourraient aussi orienter la recherche de nouvelles cibles thérapeutiques permettant l'expression de la claudine 1 dans les TNBC et ainsi augmenter leur sensibilité à la chimiothérapie.
... Contradictory to other studies showing a positive correlation between TMAO levels and depressive symptoms 55 , our results in KF patients were inconsistent. Our data in KF patients indicate that there might be sex-specific differences between TMAO levels in depressed KF patients, with depressed males having higher TMAO levels compared to females 62,63 . The accumulation of uraemic toxins is believed to weaken the GBB permitting bacterial components and uraemic toxins to enter the systemic circulation through the leaky gut. ...
... Similarly, immunostaining and immunoblotting studies of JAM-1 reported a significant decrease in JAM-1 expression in a rat model for cortical cold injury 62 . Furthermore, in human studies of preeclampsia, which is characterised by dysfunctional endothelial cell layer, noted a reduction in claudin 1, 3 and 5 signifying a disrupted endothelial barrier 63 . To further support our theory, we conducted a pilot experiment, using an isolated small artery bioassay to examine the tight-junction protein expression in non-CKD control subcutaneous fat microvessels incubated with TMAO to simulate the exposure of microvasculature to the uraemic environment. ...
Kidney failure and associated uraemia have implications for the cardiovascular system, brain, and blood–brain barrier (BBB). We aim to examine BBB disruption, by assessing brain-derived neurotropic factor (BDNF), neuron-specific enolase (NSE) levels, and gut-blood barrier (GBB) disruption by trimethylamine N-oxide (TMAO), in chronic kidney disease (CKD) patients. Additionally, endothelial tight-junction protein expressions and modulation via TMAO were assessed. Serum from chronic kidney disease (CKD) female and male haemodialysis (HD) patients, and controls, were used to measure BDNF and NSE by enzyme-linked immunosorbent assays, and TMAO by mass spectrometry. Immunofluorescent staining of subcutaneous fat biopsies from kidney transplant recipients, and controls, were used to measure microvascular expression of tight-junction proteins (claudin-5, occludin, JAM-1), and control microvasculature for TMAO effects. HD patients versus controls, had significantly lower and higher serum levels of BDNF and NSE, respectively. In CKD biopsies versus controls, reduced expression of claudin-5, occludin, and JAM-1 were observed. Incubation with TMAO significantly decreased expression of all tight-junction proteins in the microvasculature. Uraemia affects BBB and GBB resulting in altered levels of circulating NSE, BDNF and TMAO, respectively, and it also reduces expression of tight-junction proteins that confer BBB maintenance. TMAO serves as a potential candidate to alter BBB integrity in CKD.
... Different types of claudins are expressed in the placenta. The CTBs express CLDN1, CLDN3, CLDN4, and CLDN5 [124,125]; the EVTs express only CLDN3 [126] while the STB expresses CLDN4, CLDN7, CLDN8, and CLDN16 [59,127,128]. CLDN1, CLDN3, and CLDN5 are also expressed in the decidual paracellular clefts of endothelial cells [25,128,129]. Since these claudins have been demonstrated to enhance the formation of the paracellular barrier in several cell types [130], it is very possible that they form a similar barrier between trophoblast cells as well as between decidual endothelial cells to regulate the transportation of ions and solutes. ...
... The CTBs express CLDN1, CLDN3, CLDN4, and CLDN5 [124,125]; the EVTs express only CLDN3 [126] while the STB expresses CLDN4, CLDN7, CLDN8, and CLDN16 [59,127,128]. CLDN1, CLDN3, and CLDN5 are also expressed in the decidual paracellular clefts of endothelial cells [25,128,129]. Since these claudins have been demonstrated to enhance the formation of the paracellular barrier in several cell types [130], it is very possible that they form a similar barrier between trophoblast cells as well as between decidual endothelial cells to regulate the transportation of ions and solutes. The expression of the other CLDNs in the human placenta is yet to be reported. ...
... CLDN5 is downregulated during the fusion of CTB cells [124]. CLDN1, CLDN3, and CLDN5 are downregulated while CLDN16 assumes a diffused pattern of expression in the placental endothelia during preeclampsia [128]. Since placental expression and maternal serum levels of IL8 are positively associated with the severity of preeclampsia [135], and IL8 was found to decrease CLDN5 expression in the endothelia in a dose-and time-dependent manner [25], it is possible that the endothelial permeability induced by this cytokine [26] may be mediated via CLDN5 downregulation. ...
Placentation is a major determinant of the success of pregnancy. It is regulated by several factors such as cell adhesion molecules, tight junctions, and gap junctions. The cell adhesion molecules are integrins, cadherins, immunoglobulins, nectins, and selectins. The tight junctions are composed of claudins, occludin, and junction adhesion molecule proteins while the gap junctions are composed of connexins of varying molecular weights. During placentation, some of these molecules regulate trophoblast proliferation, trophoblast fusion, trophoblast migration, trophoblast invasion, trophoblast-endothelium adhesion, glandular remodeling, and spiral artery remodeling. There is a dysregulated placental expression of some of these molecules during obstetric complications. We have, hereby, indicated the expression patterns of the subunits of each of these molecules in the various trophoblast subtypes and in the decidua, and have highlighted their involvement in physiological and pathological placentation. The available evidence points to the relevance of these molecules as distinguishing markers of the various trophoblast lineages and as potential therapeutic targets in the management of malplacentation-mediated diseases. Keywords Trophoblast. Integrin. Cadherin. Immunoglobulin. Nectin. Selectin. Claudin. Occludin. Connexin. Preeclampsia Abbreviations PECAM1 platelet-endothelial cell adhesion molecule-1 VCAM1 vascular cell adhesion molecule-1 EMILIN1 elastin microfibril interface-located protein-1 ECM extracellular matrix Dsg2 desmoglein-2 Dsg3 desmoglein-3 PECAM1 platelet-endothelial cell adhesion molecule-1 NCAM neural cell adhesion molecule Mel-CAM melanoma cell adhesion molecule ICAM1 intercellular adhesion molecule-1 VCAM1 vascular cell adhesion molecule-1 ZO zonnula occludens CTB cytotrophoblast STB syncytiotrophoblast EVTs extravillous trophoblasts PCT proximal column trophoblast DCT distal column trophoblast iEVT intestitial extravillous trophoblast egEVT endoglandular extravillous trophoblast evEVT endovascular extravillous trophoblast GC giant cell dSC decidual stromal cell dNK decidual natural killer cell
... Previous study revealed that the expression of tight junction proteins is significantly changed in PE placenta compared with control placentas (Zhang et al., 2019). Liévano S, et al. found that endothelia of term human placentae display diminished expression of tight junction proteins during PE (Liévano et al., 2006). Furthermore, impaired intestinal barrier function may expose the placenta and foetus to pro-inflammatory mediators (Gohir et al., 2019). ...
Aims:
Preeclampsia (PE) affects pregnant patients worldwide, but there is no effective treatment for this condition. We aimed to explore the effect of sodium butyrate (NaB) on PE.
Methods and results:
In this study, Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) was used to induce PE in pregnant rats. We found that NaB significantly decreased the levels of blood pressure, 24-h protein urine and inflammatory factors (IL-1β, IL-6, and TGF-β), increased the fetal and placental weights and intestinal barrier markers (ZO-1, claudin-5, and occludin) expression. In addition, NaB intervention reduced the levels of soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) and increased placental growth factor (PlGF) level. Meanwhile, after NaB treatment, the Treg/Th17 ratio of immune cells in the spleen and small intestine of pregnant rats decreased, while the level of pregnancy-related DAO increased. Notably, the PE rat treatment with NaB improved gut microbiota compositions, especially for the abundances of Firmicutes and Bacteroides, and significantly increased butyric acid and pentanoic acid levels, which might help to alleviate PE in pregnant rats.
Conclusion:
In the PE rat model, exogenous NaB improved intestinal barrier function and reduced adverse outcomes, which might be associated with the gut microbiota and its production of SCFA metabolites.
Significance and impact of the study:
NaB might alleviate the adverse outcomes of PE by regulating gut microbiota and its metabolite SCFA, which revealed that NaB might be a potential regulator of gut microbiota and a therapeutic substance for PE.
... Previous studies have reported the expression of AJ and TJ proteins in chorionic villi of human placenta at term, finding that the STB expresses E-cadherin, ZO-1 and ZO-2, JAM-B, occludin, claudins -1, -3, -4, -5 -7 and -16, while the vessels in the parenchyma of chorionic villi display ZO-1, occludin, JAM-C, and claudins -1, -3, -4 and -5 [61][62][63]. ZO-1, JAM-C, and claudin-5 can be observed in large and small vessels, whereas occludin and claudins 1, -3 and -4 are mainly present in large placental vessels [61,62]. ...
... Previous studies have reported the expression of AJ and TJ proteins in chorionic villi of human placenta at term, finding that the STB expresses E-cadherin, ZO-1 and ZO-2, JAM-B, occludin, claudins -1, -3, -4, -5 -7 and -16, while the vessels in the parenchyma of chorionic villi display ZO-1, occludin, JAM-C, and claudins -1, -3, -4 and -5 [61][62][63]. ZO-1, JAM-C, and claudin-5 can be observed in large and small vessels, whereas occludin and claudins 1, -3 and -4 are mainly present in large placental vessels [61,62]. ...
... Previous studies have shown that the amount of claudins -1 and -5 present in Triton X-100 insoluble fractions, which corresponds to claudin associated with the actomyosin cytoskeleton, diminishes in preeclamptic compared to healthy placentas [61], whereas the expression of claudin-4 at the basolateral membrane of the STB diminishes in placentas derived from ZIKV-infected women [62]. ...
Clinical manifestations of coronavirus disease 2019 (COVID-19) in pregnant women are diverse, and little is known of the impact of the disease on placental physiology. Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been detected in the human placenta, and its binding receptor ACE2 is present in a variety of placental cells, including endothelium. Here, we analyze the impact of COVID-19 in placental endothelium, studying by immunofluorescence the expression of von Willebrand factor (vWf), claudin-5, and vascular endothelial (VE) cadherin in the decidua and chorionic villi of placentas from women with mild and severe COVID-19 in comparison to healthy controls. Our results indicate that: (1) vWf expression increases in the endothelium of decidua and chorionic villi of placentas derived from women with COVID-19, being higher in severe cases; (2) Claudin-5 and VE-cadherin expression decrease in the decidua and chorionic villus of placentas from women with severe COVID-19 but not in those with mild disease. Placental histological analysis reveals thrombosis, infarcts, and vascular wall remodeling, confirming the deleterious effect of COVID-19 on placental vessels. Together, these results suggest that placentas from women with COVID-19 have a condition of leaky endothelium and thrombosis, which is sensitive to disease severity.
... However, at the 3′ region of the same exon (E1d), a decreased expression in PE, but not in IUGR is observed. The same trend applies to the two more 3′ regions of exon 2, 3 and 4. The amount of the protein coded by CLDN1 is significantly reduced in PE placentas (Lievano et al. 2006). Here, we show that the two CLDN1 shortest transcripts are differentially expressed in PE, but not the longest one. ...
Two major obstetric diseases, preeclampsia (PE), a pregnancy-induced endothelial dysfunction leading to hypertension and proteinuria, and intra-uterine growth-restriction (IUGR), a failure of the fetus to acquire its normal growth, are generally triggered by placental dysfunction. Many studies have evaluated gene expression deregulations in these diseases, but none has tackled systematically the role of alternative splicing. In the present study, we show that alternative splicing is an essential feature of placental diseases, affecting 1060 and 1409 genes in PE vs controls and IUGR vs controls, respectively, many of those involved in placental function. While in IUGR placentas, alternative splicing affects genes specifically related to pregnancy, in preeclamptic placentas, it impacts a mix of genes related to pregnancy and brain diseases. Also, alternative splicing variations can be detected at the individual level as sharp splicing differences between different placentas. We correlate these variations with genetic variants to define splicing Quantitative Trait Loci (sQTL) in the subset of the 48 genes the most strongly alternatively spliced in placental diseases. We show that alternative splicing is at least partly piloted by genetic variants located either in cis (52 QTL identified) or in trans (52 QTL identified). In particular, we found four chromosomal regions that impact the splicing of genes in the placenta. The present work provides a new vision of placental gene expression regulation that warrants further studies.
