Article

Potential Role of Modifier Genes Influencing Transforming Growth Factor-β1 Levels in the Development of Vascular Defects in Endoglin Heterozygous Mice with Hereditary Hemorrhagic Telangiectasia

July 2001
American Journal Of Pathology 158(6):2011-20

July 2001
158(6):2011-20

DOI:10.1016/S0002-9440(10)64673-1

Source
PubMed

Authors:

Marie Faughnan

University of Toronto

Merry-Lynn N Mcdonald

Harvard Medical School

Show all 6 authorsHide

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder because of mutations in the genes coding for endoglin (HHT1) or ALK-1 (HHT2). The disease is associated with haploinsufficiency and a murine model was obtained by engineering mice that express a single Endoglin allele. Of a total of 171 mice that were observed for 1 year, 50 developed clinical signs of HHT. Disease prevalence was high in 129/Ola strain (72%), intermediate in the intercrosses (36%), and low in C57BL/6 backcrosses (7%). Most mice first presented with an ear telangiectasia and/or recurrent external hemorrhage. One-third of mice with HHT showed severe vascular abnormalities such as dilated vessels, hemorrhages, liver and lung congestion, and/or brain and heart ischemia. Disease sequelae included stroke, hydrocephalus, fatal hemorrhage, and congestive heart failure. Thus the murine model reproduces the multiorgan manifestations of the human disease. Levels of circulating latent transforming growth factor (TGF)-beta1 were significantly lower in the 129/Ola than in the C57BL/6 strain. Intercrosses and 129/Ola mice expressing reduced endoglin also showed lower plasma TGF-beta1 levels than control. These data suggest that modifier genes involved in the regulation of TGF-beta1 expression act in combination with a single functional copy of endoglin in the development of HHT.

Investigation of Endoglin Wild-Type and Missense Mutant Protein Heterodimerisation Using Fluorescence Microscopy Based IF, BiFC and FRET Analyses

Article

Full-text available

Jul 2014
PLOS ONE

The homodimeric transmembrane receptor endoglin (CD105) plays an important role in angiogenesis. This is highlighted by mutations in its gene, causing the vascular disorder HHT1. The main role of endoglin function has been assigned to the modulation of transforming growth factor β and bone morphogenetic protein signalling in endothelial cells. Nevertheless, other functions of endoglin have been revealed to be involved in different cellular functions and in other cell types than endothelial cells. Compared to the exploration of its natural function, little experimental data have been gathered about the mode of action of endoglin HHT mutations at the cellular level, especially missense mutations, and to what degree these might interfere with normal endoglin function. In this paper, we have used fluorescence-based microscopic techniques, such as bimolecular fluorescence complementation (BiFC), immunofluorescence staining with the endoglin specific monoclonal antibody SN6, and protein interaction studies by Förster Resonance Energy Transfer (FRET) to investigate the formation and cellular localisation of possible homo- and heterodimers composed of endoglin wild-type and endoglin missense mutant proteins. The results show that all of the investigated missense mutants dimerise with themselves, as well as with wild-type endoglin, and localise, depending on the position of the affected amino acid, either in the rough endoplasmic reticulum (rER) or in the plasma membrane of the cells. We show that the rER retained mutants reduce the amount of endogenous wild-type endoglin on the plasma membrane through interception in the rER when transiently or stably expressed in HMEC-1 endothelial cells. As a result of this, endoglin modulated TGF-β1 signal transduction is also abrogated, which is not due to TGF-β receptor ER trafficking interference. Protein interaction analyses by FRET show that rER located endoglin missense mutants do not perturb protein processing of other membrane receptors, such as TβRII, ALK5 or ALK1.

Endoglin in liver fibrogenesis: Bridging basic science and clinical practice

Article

May 2014

Endoglin, also known as cluster of differentiation CD105, was originally identified 25 years ago as a novel marker of endothelial cells. Later it was shown that endoglin is also expressed in pro-fibrogenic cells including mesangial cells, cardiac and scleroderma fibroblasts, and hepatic stellate cells. It is an integral membrane-bound disulfide-linked 180 kDa homodimeric receptor that acts as a transforming growth factor-β (TGF-β) auxiliary co-receptor. In humans, several hundreds of mutations of the endoglin gene are known that give rise to an autosomal dominant bleeding disorder that is characterized by localized angiodysplasia and arteriovenous malformation. This disease is termed hereditary hemorrhagic telangiectasia type I and induces various vascular lesions, mainly on the face, lips, hands and gastrointestinal mucosa. Two variants of endoglin (i.e., S- and L-endoglin) are formed by alternative splicing that distinguishes from each other in the length of their cytoplasmic tails. Moreover, a soluble form of endoglin, i.e., sol-Eng, is shedded by the matrix metalloprotease-14 that cleaves within the extracellular juxtamembrane region. Endoglin interacts with the TGF-β signaling receptors and influences Smad-dependent and -independent effects. Recent work has demonstrated that endoglin is a crucial mediator during liver fibrogenesis that critically controls the activity of the different Smad branches. In the present review, we summarize the present knowledge of endoglin expression and function, its involvement in fibrogenic Smad signaling, current models to investigate endoglin function, and the diagnostic value of endoglin in liver disease.

Potential Second-Hits in Hereditary Hemorrhagic Telangiectasia

Article

Full-text available

Nov 2020

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that presents with telangiectases in skin and mucosae, and arteriovenous malformations (AVMs) in internal organs such as lungs, liver, and brain. Mutations in ENG (endoglin), ACVRL1 (ALK1), and MADH4 (Smad4) genes account for over 95% of HHT. Localized telangiectases and AVMs are present in different organs, with frequencies which differ among affected individuals. By itself, HHT gene heterozygosity does not account for the focal nature and varying presentation of the vascular lesions leading to the hypothesis of a “second-hit” that triggers the lesions. Accumulating research has identified a variety of triggers that may synergize with HHT gene heterozygosity to generate the vascular lesions. Among the postulated second-hits are: mechanical trauma, light, inflammation, vascular injury, angiogenic stimuli, shear stress, modifier genes, and somatic mutations in the wildtype HHT gene allele. The aim of this review is to summarize these triggers, as well as the functional mechanisms involved.

BMP9 is a paracrine factor controlling liver sinusoidal endothelial cell fenestration and protecting from hepatic fibrosis

Article

Apr 2019

Bone morphogenetic protein 9 (BMP9) is a circulating factor produced by hepatic stellate cells that plays a critical role in vascular quiescence via its endothelial receptor ALK1. Mutations in the gene encoding ALK1 cause HHT2 (Hereditary Hemoragic Telangiectasia type 2), a rare genetic disease presenting hepatic vessel malformations. Variations of both the circulating levels and the hepatic mRNA levels of BMP9 have been recently associated with various forms of hepatic fibrosis. However, the molecular mechanism that links BMP9 with liver diseases is still unknown. Here, we report that Bmp9 gene deletion in 129/Ola mice triggers hepatic perisinusoidal fibrosis that was detectable from 15 weeks of age. An inflammatory response appeared within the same time frame as fibrosis, whereas sinusoidal vessel dilation developed later on. Proteomic and mRNA analyses of primary liver sinusoidal endothelial cells (LSECs) both revealed that the expression of the LSEC‐specifying transcription factor GATA4 was strongly reduced in Bmp9‐KO mice as compared to wild type mice. LSECs from Bmp9‐KO mice also lost the expression of several terminal differentiation markers (Lyve1, Stab1, Stab2, Ehd3, Cd209b, eNos, Maf, Plvap). They gained CD34 expression and deposited a basal lamina, indicating that they were capillarized. Another main characteristic of differentiated LSECs is the presence of permeable fenestrae. LSECs from Bmp9‐KO mice had a significantly reduced number of fenestrae. This was already observable in 2‐week‐old pups. Moreover, we could show that addition of BMP9 to primary cultures of LSECs prevented the loss of their fenestrae and maintained the expression levels of Gata4 and Plvap. Taken together, our observations show that BMP9 is a key paracrine regulator of liver homeostasis, controlling LSEC fenestration and protecting from perivascular hepatic fibrosis. This article is protected by copyright. All rights reserved.

Distinct angiostatic lung profile in endoglin and ALK1 mouse models of hereditary hemorrhagic telangiectasia

Article

Full-text available

Oct 2015

Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia associated with dysregulated angi-ogenesis and arteriovascular malformations. The disease is caused by mutations in endoglin (ENG; HHT1) or activin receptor-like kinase 1 (ALK1; HHT2) genes, coding for transforming growth factor b (TGF-b) superfamily receptors. Vascular endothelial growth factor (VEGF) has been implicated in HHT and beneficial effects of anti-VEGF treatment were recently reported in HHT patients. To investigate the systemic angiogenic phenotype of Endoglin and Alk1 mutant mice and their response to anti-VEGF therapy, we assessed microvessel density (MVD) in multiple organs after treatment with an antibody to mouse VEGF or vehicle. Lungs were the only organ showing an angiogenic defect, with reduced peripheral MVD and secondary right ventricular hypertrophy (RVH), yet distinctly associated with a fourfold increase in thrombo-spondin-1 (TSP-1) in Eng ?/-versus a rise in angiopoietin-2 (Ang-2) in Alk1 ?/-mice. Anti-VEGF treatment did reduce lung VEGF levels but interestingly, led to an increase in peripheral pulmonary MVD and attenuation of RVH; it also normalized TSP-1 and Ang-2 expression. Hepatic MVD, unaffected in mutant mice, was reduced by anti-VEGF therapy in heterozygous and wild type mice, indicating a liver-specific effect of treatment. Contrast-enhanced micro-ultrasound demonstrated a reduction in hepatic microvascular perfusion after anti-VEGF treatment only in Eng ?/-mice. Our findings indicate that the mechanisms responsible for the angiogenic imbalance and the response to anti-VEGF therapy differ between Eng and Alk1 heterozygous mice and raise the need for systemic monitoring of anti-angiogenic therapy effects in HHT patients.

Accurate genetic diagnosis of Finnish pulmonary arterial hypertension patients using oligonucleotide-selective sequencing

Article

Full-text available

Apr 2015

The genetic basis of pulmonary arterial hypertension (PAH) among Finnish PAH patients is poorly understood. We adopted a novel-targeted next-generation sequencing (NGS) approach called Oligonucleotide-Selective Sequencing (OS-Seq) and developed a custom data analysis and interpretation pipeline to identify pathogenic base substitutions, insertions, and deletions in seven genes associated with PAH (BMPR2, BMPR1B, ACVRL1, ENG, SMAD9, CAV1, and KCNK3) from Finnish PAH patients. This study represents the first clinical study with OS-Seq technology on patients suffering from a rare genetic disorder. We analyzed DNA samples from 21 Finnish PAH patients, whose BMPR2 and ACVRL1 mutation status had been previously studied using Sanger sequencing. Our sequencing panel covered 100% of the targeted base pairs with >15× sequencing depth. Pathogenic base substitutions were identified in the BMPR2 gene in 29% of the Finnish PAH cases. Two of the pathogenic variant-positive patients had been previously tested negative using Sanger sequencing. No clinically significant variants were identified in the six other PAH genes. Our study validates the use of targeted OS-Seq for genetic diagnostics of PAH and revealed pathogenic variants that had been previously missed using Sanger sequencing.

Endoglin and activin receptor-like kinase 1 heterozygous mice have a distinct pulmonary and hepatic angiogenic profile and response to anti-VEGF treatment

Article

Full-text available

Sep 2013
Angiogenesis

Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia associated with dysregulated angiogenesis and arteriovascular malformations. The disease is caused by mutations in endoglin (ENG; HHT1) or activin receptor-like kinase 1 (ALK1; HHT2) genes, coding for transforming growth factor β (TGF-β) superfamily receptors. Vascular endothelial growth factor (VEGF) has been implicated in HHT and beneficial effects of anti-VEGF treatment were recently reported in HHT patients. To investigate the systemic angiogenic phenotype of Endoglin and Alk1 mutant mice and their response to anti-VEGF therapy, we assessed microvessel density (MVD) in multiple organs after treatment with an antibody to mouse VEGF or vehicle. Lungs were the only organ showing an angiogenic defect, with reduced peripheral MVD and secondary right ventricular hypertrophy (RVH), yet distinctly associated with a fourfold increase in thrombospondin-1 (TSP-1) in Eng (+/-) versus a rise in angiopoietin-2 (Ang-2) in Alk1 (+/-) mice. Anti-VEGF treatment did reduce lung VEGF levels but interestingly, led to an increase in peripheral pulmonary MVD and attenuation of RVH; it also normalized TSP-1 and Ang-2 expression. Hepatic MVD, unaffected in mutant mice, was reduced by anti-VEGF therapy in heterozygous and wild type mice, indicating a liver-specific effect of treatment. Contrast-enhanced micro-ultrasound demonstrated a reduction in hepatic microvascular perfusion after anti-VEGF treatment only in Eng (+/-) mice. Our findings indicate that the mechanisms responsible for the angiogenic imbalance and the response to anti-VEGF therapy differ between Eng and Alk1 heterozygous mice and raise the need for systemic monitoring of anti-angiogenic therapy effects in HHT patients.

From remodeling to quiescence: The transformation of the vascular network

Article

Aug 2021

The vascular system is essential for embryogenesis, healing, and homeostasis. Dysfunction or deregulated blood vessel function contributes to multiple diseases, including diabetic retinopathy, cancer, hypertension, or vascular malformations. A balance between the formation of new blood vessels, vascular remodeling, and vessel quiescence is fundamental for tissue growth and function. Whilst the major mechanisms contributing to the formation of new blood vessels have been well explored in recent years, vascular remodeling and quiescence remain poorly understood. In this review, we highlight the cellular and molecular mechanisms responsible for vessel remodeling and quiescence during angiogenesis. We further underline how impaired remodeling and/or destabilization of vessel networks can contribute to vascular pathologies. Finally, we speculate how addressing the molecular mechanisms of vascular remodeling and stabilization could help to treat vascular-related disorders.

Thresholds of Endoglin Expression in Endothelial Cells Explains Vascular Etiology in Hereditary Hemorrhagic Telangiectasia Type 1

Article

Full-text available

Aug 2021

Hereditary Hemorrhagic Telangiectasia type 1 (HHT1) is an autosomal dominant inherited disease characterized by arteriovenous malformations and hemorrhage. HHT1 is caused by mutations in ENDOGLIN, which encodes an ancillary receptor for Transforming Growth Factor-β/Bone Morphogenetic Protein-9 expressed in all vascular endothelial cells. Haploinsufficiency is widely accepted as the underlying mechanism for HHT1. However, it remains intriguing that only some, but not all, vascular beds are affected, as these causal gene mutations are present in vascula-ture throughout the body. Here, we have examined the endoglin expression levels in the blood vessels of multiple organs in mice and in humans. We found a positive correlation between low basal levels of endoglin and the general prevalence of clinical manifestations in selected organs. Endoglin was found to be particularly low in the skin, the earliest site of vascular lesions in HHT1, and even undetectable in the arteries and capillaries of heterozygous endoglin mice. Endoglin levels did not appear to be associated with organ-specific vascular functions. Instead, our data revealed a critical endoglin threshold compatible with the haploinsufficiency model, below which endothelial cells independent of their tissue of origin exhibited abnormal responses to Vascular Endothelial Growth Factor. Our results support the development of drugs promoting endoglin expression as potentially protective.

BMP9 and BMP10: Two close vascular quiescence partners that stand out

Article

Full-text available

Jul 2021
DEV DYNAM

Bone morphogenetic proteins (BMPs) are dimeric transforming growth factor ß (TGFß) family cytokines that were first described in bone and cartilage formation but have since been shown to be involved in many pleiotropic functions. In human, there are 15 BMP ligands, which initiate their cellular signaling by forming a complex with two copies of type I receptors and two copies of type II receptors, both of which are transmembrane receptors with an intracellular serine/threonine kinase domain. Within this receptor family, ALK1 (activin receptor‐like kinase 1), which is a type I receptor mainly expressed on endothelial cells, and BMPRII (BMP Receptor type II), a type II receptor also highly expressed on endothelial cells, have been directly linked to two rare vascular diseases: hereditary hemorrhagic telangiectasia (HHT), and pulmonary arterial hypertension (PAH), respectively. BMP9 (gene name GDF2) and BMP10, two close members of the BMP family, are the only known ligands for the ALK1 receptor. This specificity gives them a unique role in physiological and pathological angiogenesis and tissue homeostasis. The aim of this current review is to present an overview of what is known about BMP9 and BMP10 on vascular regulation with a particular emphasis on recent results and the many questions that remain unanswered regarding the roles and specificities between BMP9 and BMP10.

Endoglin: An ‘Accessory’ Receptor Regulating Blood Cell Development and Inflammation

Article

Full-text available

Dec 2020
INT J MOL SCI

Transforming growth factor-β1 (TGF-β1) is a pleiotropic factor sensed by most cells. It regulates a broad spectrum of cellular responses including hematopoiesis. In order to process TGF-β1-responses in time and space in an appropriate manner, there is a tight regulation of its signaling at diverse steps. The downstream signaling is mediated by type I and type II receptors and modulated by the ‘accessory’ receptor Endoglin also termed cluster of differentiation 105 (CD105). Endoglin was initially identified on pre-B leukemia cells but has received most attention due to its high expression on activated endothelial cells. In turn, Endoglin has been figured out as the causative factor for diseases associated with vascular dysfunction like hereditary hemorrhagic telangiectasia-1 (HHT-1), pre-eclampsia, and intrauterine growth restriction (IUPR). Because HHT patients often show signs of inflammation at vascular lesions, and loss of Endoglin in the myeloid lineage leads to spontaneous inflammation, it is speculated that Endoglin impacts inflammatory processes. In line, Endoglin is expressed on progenitor/precursor cells during hematopoiesis as well as on mature, differentiated cells of the innate and adaptive immune system. However, so far only pro-monocytes and macrophages have been in the focus of research, although Endoglin has been identified in many other immune system cell subsets. These findings imply a functional role of Endoglin in the maturation and function of immune cells. Aside the functional relevance of Endoglin in endothelial cells, CD105 is differentially expressed during hematopoiesis, arguing for a role of this receptor in the development of individual cell lineages. In addition, Endoglin expression is present on mature immune cells of the innate (i.e., macrophages and mast cells) and the adaptive (i.e., T-cells) immune system, further suggesting Endoglin as a factor that shapes immune responses. In this review, we summarize current knowledge on Endoglin expression and function in hematopoietic precursors and mature hematopoietic cells of different lineages.

Biglycan in the Skeleton

Article

Jul 2020

Small leucine rich proteoglycans (SLRPs), including Biglycan, have key roles in many organ and tissue systems. The goal of this article is to review the function of Biglycan and other related SLRPs in mineralizing tissues of the skeleton. The review is divided into sections that include Biglycan’s role in structural biology, signaling, craniofacial and long bone homeostasis, remodeled skeletal tissues, and in human genetics. While many cell types in the skeleton are now known to be affected by Biglycan, there are still unanswered questions about its mechanism of action(s).

Differential Consequences of Bmp9 Deletion on Sinusoidal Endothelial Cell Differentiation and Liver Fibrosis in 129/Ola and C57BL/6 Mice

Article

Full-text available

Sep 2019

The aim of the present work was to address the role of BMP9 in different genetic backgrounds (C57BL/6, BALB/c, and 129/Ola) of mice deleted for Bmp9. We found that Bmp9 deletion led to premature mortality only in the 129/Ola strain. We have previously shown that Bmp9 deletion led to liver sinusoidal endothelial cells (LSEC) capillarization and liver fibrosis in the 129/Ola background. Here, we showed that this is not the case in the C57BL/6 background. Analysis of LSEC from Wild-type (WT) versus Bmp9-KO mice in the C57BL/6 background showed no difference in LSEC fenestration and in the expression of differentiation markers. Comparison of the mRNA expression of LSEC differentiation markers between WT C57BL/6 and 129/Ola mice showed a significant decrease in Stabilin2, Plvap, and CD209b, suggesting a more capillary-like phenotype in WT C57BL/6 LSECs. C57BL/6 mice also had lower BMP9 circulating concentrations and hepatic Vegfr2 mRNA levels, compared to the 129/Ola mice. Taken together, our observations support a role for BMP9 in liver endothelial cell fenestration and prevention of fibrosis that is dependent on genetic background. It also suggests that 129/Ola mice are a more suitable model than C57BL/6 for the study of liver fibrosis subsequent to LSEC capillarization.

Inhibiting DPP4 in a mouse model of HHT1 results in a shift towards regenerative macrophages and reduces fibrosis after myocardial infarction

Article

Full-text available

Dec 2017
PLOS ONE

Aims Hereditary Hemorrhagic Telangiectasia type-1 (HHT1) is a genetic vascular disorder caused by haploinsufficiency of the TGFβ co-receptor endoglin. Dysfunctional homing of HHT1 mononuclear cells (MNCs) towards the infarcted myocardium hampers cardiac recovery. HHT1-MNCs have elevated expression of dipeptidyl peptidase-4 (DPP4/CD26), which inhibits recruitment of CXCR4-expressing MNCs by inactivation of stromal cell-derived factor 1 (SDF1). We hypothesize that inhibiting DPP4 will restore homing of HHT1-MNCs to the infarcted heart and improve cardiac recovery. Methods and results After inducing myocardial infarction (MI), wild type (WT) and endoglin heterozygous (Eng+/-) mice were treated for 5 days with the DPP4 inhibitor Diprotin A (DipA). DipA increased the number of CXCR4⁺ MNCs residing in the infarcted Eng+/- hearts (Eng+/- 73.17±12.67 vs. Eng+/- treated 157.00±11.61, P = 0.0003) and significantly reduced infarct size (Eng+/- 46.60±9.33% vs. Eng+/- treated 27.02±3.04%, P = 0.03). Echocardiography demonstrated that DipA treatment slightly deteriorated heart function in Eng+/- mice. An increased number of capillaries (Eng+/- 61.63±1.43 vs. Eng+/- treated 74.30±1.74, P = 0.001) were detected in the infarct border zone whereas the number of arteries was reduced (Eng+/- 11.88±0.63 vs. Eng+/- treated 6.38±0.97, P = 0.003). Interestingly, while less M2 regenerative macrophages were present in Eng+/- hearts prior to DipA treatment, (WT 29.88±1.52% vs. Eng+/- 12.34±1.64%, P<0.0001), DPP4 inhibition restored the number of M2 macrophages to wild type levels. Conclusions In this study, we demonstrate that systemic DPP4 inhibition restores the impaired MNC homing in Eng+/- animals post-MI, and enhances cardiac repair, which might be explained by restoring the balance between the inflammatory and regenerative macrophages present in the heart.

Pathobiology of Human Cerebrovascular Malformations: Basic Mechanisms and Clinical Relevance

Article

Jul 2004

CEREBROVASCULAR MALFORMATIONS AFFECT more than 3% of the population, exposing them to a lifetime risk of hemorrhagic stroke, seizures, and focal neurological deficits. Cerebral cavernous malformations (CCMs) exhibit an immature vessel wall, a brittle hemorrhagic tendency, and epileptogenesis, whereas arteriovenous malformations (AVMs) lack capillary beds and manifest apoplectic bleeding under high-flow conditions. There are also more benign venous anomalies, capillary malformations, and lesions with mixed and transitional features. Advances have been made toward understanding the natural history, radiological and pathological correlates, and clinical management. Yet, mechanisms of lesion genesis and clinical manifestations remain largely unknown, and the clinical behavior in individual patients is highly unpredictable. Lesion pathogenesis likely involves abnormal assembly or maintenance of blood vessels, resulting in dysmorphic vessel phenotypes. Familial CCM disease is in part caused by mutations in a cytoskeletal-related protein that is likely integral to interendothelial cell connectivity and maturation of the vascular wall. Rare familial forms of AVM disease have been correlated with two different transforming growth factor-β receptor components, possibly causing disturbance in signaling during vascular assembly. Relevance of these mechanisms to the more common and otherwise identical sporadic CCM and AVM lesions is being explored. In this report, basic mechanisms of vasculogenesis and angiogenesis and how they possibly relate to the common cerebrovascular malformation lesions are reviewed. Novel concepts are discussed related to the cellular, molecular, and genetic substrates in CCM and AVM as well as to how this knowledge can be applied to predict, explain, and possibly modify clinical disease manifestations.

The Nuclear Hormone Receptor Gene Nr2c1 (Tr2) is a Critical Regulator of Early Retina Cell Patterning

Article

Full-text available

May 2017
DEV BIOL

Nuclear hormone receptors play a major role in the development of many tissues. This study uncovers a novel role for testicular receptor 2 (Tr2, Nr2c1) in defining the early phase of retinal development and regulating normal retinal cell patterning and topography. The mammalian retina undergoes an overlapping yet biphasic period of development to generate all seven retinal cell types. We discovered that Nr2c1 expression coincides with development of the early retinal cells. Loss of Nr2c1 causes a severe vision deficit and impacts early, but not late retina cell types. Retinal cone cell topography is disrupted with an increase in displaced amacrine cells. Additionally, genetic background significantly impacts phenotypic outcome of cone photoreceptor cells but not amacrine cells. Chromatin-IP experiments reveal NR2C1 regulates early cell transcription factors that regulate retinal progenitor cells during development, including amacrine (Satb2) and cone photoreceptor regulators thyroid and retinoic acid receptors. This study supports a role for Nr2c1 in defining the biphasic period of retinal development and specifically influencing the early phase of retinal cell fate.

Bone Morphogenetic Proteins in Vascular Homeostasis and Disease

Article

Mar 2017

It is well established that control of vascular morphogenesis and homeostasis is regulated by vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), Delta-like 4 (Dll4), angiopoietin, and ephrin signaling. It has become clear that signaling by bone morphogenetic proteins (BMPs), which have a long history of studies in bone and early heart development, are also essential for regulating vascular function. Indeed, mutations that cause deregulated BMP signaling are linked to two human vascular diseases, hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension. These observations are corroborated by data obtained with vascular cells in cell culture and in mouse models. BMPs are required for normal endothelial cell differentiation and for venous/arterial and lymphatic specification. In adult life, BMP signaling orchestrates neo-angiogenesis as well as vascular inflammation, remodeling, and calcification responses to shear and oxidative stress. This review emphasizes the pivotal role of BMPs in the vascular system, based on studies of mouse models and human vascular disorders.

TGF-? Signaling in Control of Cardiovascular Function

Article

Mar 2017

Genetic studies in animals and humans indicate that gene mutations that functionally perturb transforming growth factor ? (TGF-?) signaling are linked to specific hereditary vascular syndromes, including Osler-Rendu-Weber disease or hereditary hemorrhagic telangiectasia and Marfan syndrome. Disturbed TGF-? signaling can also cause nonhereditary disorders like atherosclerosis and cardiac fibrosis. Accordingly, cell culture studies using endothelial cells or smooth muscle cells (SMCs), cultured alone or together in two- or three-dimensional cell culture assays, on plastic or embedded in matrix, have shown that TGF-? has a pivotal effect on endothelial and SMC proliferation, differentiation, migration, tube formation, and sprouting. Moreover, TGF-? can stimulate endothelial-to-mesenchymal transition, a process shown to be of key importance in heart valve cushion formation and in various pathological vascular processes. Here, we discuss the roles of TGF-? in vasculogenesis, angiogenesis, and lymphangiogenesis and the deregulation of TGF-? signaling in cardiovascular diseases.

Contribution of oxidative stress to endothelial dysfunction in hereditary hemorrhagic telangiectasia

Article

Full-text available

Feb 2015

Oxidative stress causes endothelial dysfunction and is implicated in the pathogenesis of cardiovascular diseases. Our studies suggested that reactive oxygen species (ROS) play a crucial role in hereditary hemorrhagic telangiectasia (HHT) disease, a vascular dysplasia affecting 1 in 5,000–8,000 people. Mutations in endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1) genes are responsible for HHT1 and HHT2 and are associated with arteriovenous malformations. ENG and ACVRL1 interact with endothelial nitric oxide synthase (eNOS) and regulate its activation. Mice heterozygous for these genes (Eng+/– and Acvrl1+/–) show reduced ENG or ACVRL1 protein levels in endothelial cells causing eNOS uncoupling, generation of ROS rather than nitric oxide (NO•), leading to impaired NO• mediated vasodilation. ROS production is increased in several organs of Eng+/– and Acvrl1+/– mice, including lungs, liver, and colon, affected in HHT. The major source of increased oxidative stress in these tissues is eNOS-derived ROS and not mitochondrial or NADPH oxidase-dependent ROS. Eng+/– and Acvrl1+/– mice also develop with age signs of pulmonary arterial hypertension attributable to eNOS-derived ROS, which was preventable by antioxidant treatment. To date, only one pilot study has been carried out in HHT patients, and it showed beneficial effects of antioxidant therapy on epistaxis. We suggest that more clinical studies are warranted to investigate whether antioxidants would prevent, delay or attenuate manifestations of disease in individuals with HHT, based on our experimental data in mouse models.

Integrin β8 Deletion Enhances Vascular Dysplasia and Hemorrhage in the Brain of Adult Alk1 Heterozygous Mice

Article

Full-text available

Dec 2016

Brain arteriovenous malformation (bAVM), characterized by tangled dysplastic vessels, is an important cause of intracranial hemorrhage in young adults, and its pathogenesis and progression are not fully understood. Patients with haploinsufficiency of transforming growth factor-β (TGF-β) receptors, activin receptor-like kinase 1 (ALK1) or endoglin (ENG) have a higher incidence of bAVM than the general population. However, bAVM does not develop effectively in mice with the same haploinsufficiency. The expression of integrin β8 subunit (ITGB8), another member in the TGF-β superfamily, is reduced in sporadic human bAVM. Brain angiogenic stimulation results at the capillary level of vascular malformation in adult Alk1 haploinsufficient (Alk1 +/− ) mice. We hypothesized that deletion of Itgb8 enhances bAVM development in adult Alk1 +/− mice. An adenoviral vector expressing Cre recombinase (Ad-Cre) was co-injected with an adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF) into the brain of Alk1 +/−;Itgb8-floxed mice to induce focal Itgb8 gene deletion and angiogenesis. We showed that compared with Alk +/− mice (4.75 ± 1.38/mm2), the Alk1 +/−;Itgb8-deficient mice had more dysplastic vessels in the angiogenic foci (7.14 ± 0.68/mm2, P = 0.003). More severe hemorrhage was associated with dysplastic vessels in the brain of Itgb8-deleted Alk1 +/− , as evidenced by larger Prussian blue-positive areas (1278 ± 373 pixels/mm2 vs. Alk1 +/− : 320 ± 104 pixels/mm2; P = 0.028). These data indicate that both Itgb8 and Alk1 are important in maintaining normal cerebral angiogenesis in response to VEGF. Itgb8 deficiency enhances the formation of dysplastic vessels and hemorrhage in Alk1 +/− mice.

Pathogenesis of Brain Arteriovenous Malformations

Article

Full-text available

Apr 2016
NEUROL MED-CHIR

Masaki Komiyama

Brain arteriovenous malformations (bAVMs) represent a high risk of intracranial hemorrhages, which are substantial causes of morbidity and mortality of bAVMs, especially in children and young adults. Although a variety of factors leading to hemorrhages of bAVMs are investigated extensively, their pathogenesis is still not well elucidated. The author has reviewed the updated data of genetic aspects of bAVMs, especially focusing on clinical and experimental knowledge from hereditary hemorrhagic telangiectasia, which is the representative genetic disease presenting with bAVMs caused by loss-of-function in one of the two genes: endoglin and activin receptor-like kinase 1. This knowledge may allow us to infer the pathogensis of sporadic bAVMs and in the development of new medical therapies for them.

TGF-β and Cardiovascular Disorders

Chapter

Full-text available

May 2013

Transforming growth factor β (TGF-β) is a secreted pleiotropic cytokine that is involved in a wide range of biological processes and has essential roles in development and tissue homeostasis. TGF-β elicits cellular effects by activating serine/threonine kinase receptors located at the plasma membrane and intracellular Smad effector proteins. TGF-β is an important (cardio)vascular regulator as shown by many in vitro studies on cultured endothelial and mural cells, in vivo studies in animal models, and genetic studies in which mutations in human TGF-β signaling components have been causally linked to cardiovascular diseases. Here we review recent progress in our understanding of the (dys)function of TGF-β in the cardiovascular system.

Research on potential biomarkers in hereditary hemorrhagic telangiectasia

Article

Full-text available

Mar 2015

Hereditary hemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder, involving mutations in two predominant genes known as Endoglin (ENG; HHT1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT2), as well as in some less frequent genes, such as MADH4/SMAD4 (JP-HHT) or BMP9/GDF2 (HHT5). The diagnosis of HHT patients currently remains at the clinical level, according to the “Curaçao criteria,” whereas the molecular diagnosis is used to confirm or rule out suspected HHT cases, especially when a well characterized index case is present in the family or in an isolated population. Unfortunately, many suspected patients do not present a clear HHT diagnosis or do not show pathogenic mutations in HHT genes, prompting the need to investigate additional biomarkers of the disease. Here, several HHT biomarkers and novel methodological approaches developed during the last years will be reviewed. On one hand, products detected in plasma or serum samples: soluble proteins (vascular endothelial growth factor, transforming growth factor β1, soluble endoglin, angiopoietin-2) and microRNA variants (miR-27a, miR-205, miR-210). On the other hand, differential HHT gene expression fingerprinting, next generation sequencing of a panel of genes involved in HHT, and infrared spectroscopy combined with artificial neural network patterns will also be reviewed. All these biomarkers might help to improve and refine HHT diagnosis by distinguishing from the non-HHT population.

Pericytes as targets in hereditary hemorrhagic telangiectasia

Article

Full-text available

Feb 2015

Defective paracrine Transforming Growth Factor-β (TGF-β) signaling between endothelial cells and the neighboring mural cells have been thought to lead to the development of vascular lesions that are characteristic of Hereditary Hemorrhagic Telangiectasia (HHT). This review highlights recent progress in our understanding of TGF-β signaling in mural cell recruitment and vessel stabilization and how perturbed TGF-β signaling might contribute to defective endothelial-mural cell interaction affecting vessel functionalities. Our recent findings have provided exciting insights into the role of thalidomide, a drug that reduces both the frequency and the duration of epistaxis in individuals with HHT by targeting mural cells. These advances provide opportunities for the development of new therapies for vascular malformations.

2014 MI MAK

Data

Aug 2014

Impaired Resolution of Inflammation in the Endoglin Heterozygous Mouse Model of Chronic Colitis

Article

Full-text available

Jul 2014
MEDIAT INFLAMM

Endoglin is a coreceptor of the TGF-β superfamily predominantly expressed on the vascular endothelium and selective subsets of immune cells. We previously demonstrated that Endoglin heterozygous (Eng +/−) mice subjected to dextran sulfate sodium (DSS) developed persistent gut inflammation and pathological angiogenesis. We now report that colitic Eng +/− mice have low colonic levels of active TGF-β1, which was associated with reduced expression of thrombospondin-1, an angiostatic factor known to activate TGF-β1. We also demonstrate dysregulated expression of BMPER and follistatin, which are extracellular regulators of the TGF-β superfamily that modulate angiogenesis and inflammation. Heightened colonic levels of the neutrophil chemoattractant and proangiogenic factor, CXCL1, were also observed in DSS-treated Eng +/− mice. Interestingly, despite increased macrophage and neutrophil infiltration, a gut-specific reduction in expression of the key phagocytic respiratory burst enzymes, NADPH oxidase 2 (Nox-2) and myeloperoxidase, was seen in Eng +/− mice undergoing persistent inflammation. Taken together, these findings suggest that endoglin is required for TGF-β superfamily mediated resolution of inflammation and fully functional myeloid cells.

Immunohistochemical Localization and Characterization of Putative Mesenchymal Stem Cell Markers in the Retinal Capillary Network of Rodents

Article

Full-text available

Apr 2013
CELLS TISSUES ORGANS

Perivascular cells of microvascular niches are the prime candidates for being a reservoire of mesenchymal stem cell (MSC)-like cells in many tissues and organs that could serve as a potential source of cells and a target of novel cell-based therapeutic approaches. In the present study, by utilising typical markers of pericytes (neuronal-glial antigen 2, NG2, a chondroitin sulphate proteoglycan) and those of MSCs (CD146 and CD105) and primitive pluripotent cells (sex-determining region Y-box 2, Sox2), the phenotypic traits and the distribution of murine and rat retinal perivascular cells were investigated in situ. Our findings indicate that retinal microvessels of juvenile rodents are highly covered by NG2-positive branching processes of pericytic (perivascular) cells that are less prominent in mature capillary networks of the adult retina. In the adult rodent retinal vascular bed, NG2 labeling is mainly confined to membranes of the cell body resulting in a pearl-chain-like distribution along the vessels. Retinal pericytes, which were identified by their morphology and NG2 expression, simultaneously express CD146. Furthermore, CD146-positive cells located at small arteriole-to-capillary branching points appear more intensely stained than elsewhere. Evidence for a differential expression of the two markers around capillaries that would hint at a clonal heterogeneity among pericytic cells, however, is lacking. In contrast, the expression of CD105 is exclusively restricted to vascular endothelial cells and Sox2 is detected neither in perivascular nor in endothelial cells. In dissociated retinal cultures, however, simultaneous expression of NG2 and CD105 was observed. Collectively, our data indicate that vascular wall resident retinal pericytes share some phenotypic features (i.e. CD146 expression) with archetypal MSCs, which is even more striking in dissociated retinal cultures (i.e. CD105 expression). These findings might have implications for the treatment of retinal pathologies.

Cyst expansion and regression in a mouse model of polycystic kidney disease

Article

Full-text available

Mar 2013
KIDNEY INT

Autosomal-dominant polycystic kidney disease is characterized by progressive cyst formation and fibrosis in the kidneys. Here we describe an orthologous Pkd1nl,nl mouse model, with reduced expression of the normal Pkd1 transcript, on a fixed genetic background of equal parts C57Bl/6 and 129Ola/Hsd mice (B6Ola-Pkd1nl,nl). In these mice, the first cysts develop from mature proximal tubules around birth. Subsequently, larger cysts become visible at day 7, followed by distal tubule and collecting duct cyst formation, and progressive cystic enlargement to develop into large cystic kidneys within 4 weeks. Interestingly, cyst expansion was followed by renal volume regression due to cyst collapse. This was accompanied by focal formation of fibrotic areas, an increased expression of genes involved in matrix remodeling and subsequently an increase in infiltrating immune cells. After an initial increase in blood urea within the first 4 weeks, renal function remained stable over time and the mice were able to survive up to a year. Also, in kidneys of ADPKD patients collapsed cysts were observed, in addition to massive fibrosis and immune infiltrates. Thus, B6Ola-Pkd1nl,nl mice show regression of cysts and renal volume that is not accompanied by a reduction in blood urea levels.Kidney International advance online publication, 6 March 2013; doi:10.1038/ki.2013.13.

BMP9 is a key player in endothelial identity and its loss is sufficient to induce arteriovenous malformations

Article

Mar 2024
CARDIOVASC RES

Aims BMP9 is a high affinity ligand of ALK1 and endoglin receptors that are mutated in the rare genetic vascular disorder Hereditary Hemorrhagic Telangiectasia (HHT). We have previously shown that loss of Bmp9 in the 129/Ola genetic background leads to spontaneous liver fibrosis via capillarization of liver sinusoidal endothelial cells (LSEC) and kidney lesions. We aimed to decipher the molecular mechanisms downstream of BMP9 to better characterize its role in vascular homeostasis in different organs. Methods and results For this, we performed a RNAseq analysis on LSEC from adult WT and Bmp9-KO mice and identified over 2000 differentially expressed genes. Gene ontology analysis showed that Bmp9 deletion led to a decrease in BMP and Notch signaling, but also LSEC capillary identity while increasing their cell cycle. The gene ontology term “glomerulus development” was also negatively enriched in Bmp9-KO mice versus WT supporting a role for BMP9 in kidney vascularization. Through different imaging approaches (electron microscopy, immunostainings), we found that loss of Bmp9 led to vascular enlargement of the glomeruli capillaries associated with alteration of podocytes. Importantly, we also showed for the first time that the loss of Bmp9 led to spontaneous arteriovenous malformations (AVMs) in the liver, gastro-intestinal tract and uterus. Conclusions Altogether, these results demonstrate that BMP9 plays an important role in vascular quiescence both locally in the liver by regulating endothelial capillary differentiation markers and cell cycle but also at distance in many organs via its presence in the circulation. It also reveals that loss of Bmp9 is sufficient to induce spontaneous AVMs, supporting a key role for BMP9 in the pathogenesis of HHT.

Pathobiology of True Arteriovenous Malformations

Chapter

Jan 2011

Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)

Chapter

Jan 2020

Pericytes in Hereditary Hemorrhagic Telangiectasia

Chapter

May 2019

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by multi-systemic vascular dysplasia affecting 1 in 5000 people worldwide. Individuals with HHT suffer from many complications including nose and gastrointestinal bleeding, anemia, iron deficiency, stroke, abscess, and high-output heart failure. Identification of the causative gene mutations and the generation of animal models have revealed that decreased transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signaling and increased vascular endothelial growth factor (VEGF) signaling activity in endothelial cells are responsible for the development of the vascular malformations in HHT. Perturbations in these key pathways are thought to lead to endothelial cell activation resulting in mural cell disengagement from the endothelium. This initial instability state causes the blood vessels to response inadequately when they are exposed to angiogenic triggers resulting in excessive blood vessel growth and the formation of vascular abnormalities that are prone to bleeding. Drugs promoting blood vessel stability have been reported as effective in preclinical models and in clinical trials indicating possible interventional targets based on a normalization approach for treating HHT. Here, we will review how disturbed TGF-β and VEGF signaling relates to blood vessel destabilization and HHT development and will discuss therapeutic opportunities based on the concept of vessel normalization to treat HHT.

Hereditary Hemorrhagic Telangiectasia

Article

Jun 2016

Joseph G Parambil

Hereditary hemorrhagic telangiectasia (HHT) is an underrecognized and underdiagnosed autosomal-dominant angiodysplasia that has an estimated prevalence of 1 in 5000 individuals, with variable clinical presentations even within family members with identical mutations. The most common manifestations are telangiectasias of the skin and nasal mucosa. However, HHT can often be complicated by the presence of arteriovenous malformations and telangiectasias in the lungs, brain, gastrointestinal tract, and liver that are often silent and can lead to life-threatening complications of stroke and hemorrhage. This article reviews HHT for the pulmonologist, who is not uncommonly the first practitioner to encounter these patients.

A case of Hereditary Hemorrhasic Telangiectasia (Rendu-Osler-Weber disease) with gastric hemorrhagic lesions successfully treated by Algon plasma coagulation

Article

Oct 2003

A 47-year-old man was admitted to our hospital with the chief complaint of frequent nasal bleeding. Several telangiectatic lesions were observed both on his skin and on his oral mucosa. His father had not only similarly experienced frequent nasal bleeding but also had similar skin lesions as those demonstrated by the patient. We, therefore, made a diagnosis of Hereditary Hemorrhagic Telangiectasia (Rendu-Osler-Weber disease: ROW disease). Upper gastrointestinal endoscopy revealed a number of hemorrhagic telangiectasia lesions throughout the stomach which are considered to cause chronic anemia. Argon plasma coagulation was used to treat the hemorrhagic telangiectasia, with which resulted in an improvement of his anemia. He also demonstrated a couple of pulmonary arteriovenus malformations (p-AVM) and multiple hepatic hemangiomatous lesions associated with ROW disease. Since he also suffered from exartional dyspnea with hypoxia due to p-AVM, embolization with platinum coils was performed to treat the p-AVM. The argon plasma coagulation method is considered to be an effective treatment for gastric lesions in ROW disease.

Arteriovenous Patterning in the Vascular System

Article

Dec 2010

Thomas Gridley

This chapter discusses arteriovenous patterning in the vascular system. One of the primary distinctions in the mammalian vasculature is its division into arterial and venous systems. These simple diagrams underscore the functional, anatomical and structural differences that exist between arteries and veins. While both vessel types are lined by a thin inner layer of endothelial cells, arteries have a thicker vessel wall with more elastic fibers and vascular smooth muscle cells to support the higher blood pressure in arteries. Veins, on the other hand, contain valves to prevent retrograde flow of blood. Acquisition of these morphological and structural differences has long been attributed to the physiological factors that differ between these two vessel types. Recent work has established that, contrary to the historic view, genetic prepatterning prior to the onset of circulation is a primary determinant in regulating the differentiation of arteries and veins. However, this genetic prepattern is plastic, and is modified and optimized by environmental cues such as hemodynamic flow.

Hereditary Hemorrhagic Telangiectasia

Article

Nov 2014
Clin Pulm Med

Joseph G Parambil

Hereditary hemorrhagic telangiectasia (HHT) or Osler-Weber-Rendu syndrome is an inherited angiodysplasia through autosomal dominance that is underrecognized as well as underdiagnosed in the general population. It has an estimated prevalence of at least 1 in 5000 individuals and displays an age-dependent penetrance along with a variable clinical presentation, even within family members with identical mutations. It most commonly manifests with the presence of telangiectasias of the skin and the nose, and is frequently complicated by the presence of arteriovenous malformations and telangiectasias in the brain, lungs, gastrointestinal tract, and liver. These internal manifestations can often be silent and lead to life-threatening complications of stroke and hemorrhage. Medical care for patients with HHT is improving today due to greater understanding of causative genetics and disease pathobiology as well as the establishment of dedicated HHT centers that, through a multidisciplinary approach, screen for and treat the various manifestations of this disorder. The purpose of this review is to go over the diagnosis of HHT, prevention of disease-related complications, and treatment of symptomatic disease.

Arteriovenous Malformation in Mice and Men

Article

Jan 2008

Arteriovenous malformations are the most dangerous vascular malformations and extremely difficult to treat. While most of them are sporadic, some are associated with autosomal dominant disorders, such as hereditary hemorrhagic telangiectasia, PTEN hamartoma tumor syndrome, and capillary malformation-arteriovenous malformation. Although important advances have been made in the diagnosis and treatment of arteriovenous malformations, the pathogenic mechanisms remain poorly understood. Yet, this is an essential step towards the development of targeted therapies. Here, we discuss the most recent insights on arteriovenous malformations, on the basis of studies on arteriovenous differentiation in animal models, and the monogenic disorders with a predisposition to arteriovenous malformations.

Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome)

Article

Dec 2013

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant, highly penetrant and variable multisystem disorder due to maldevelopment of capillaries. The condition used to be called Osler–Weber–Rendu syndrome. The major features are epistaxis; mucocutaneous telangiectasias; and visceral arteriovenous malformations (especially in the brain, gastrointestinal tract, liver and lung). The causes defined thus far are in genes involved in signaling through the transforming growth factor β/bone morphogenetic protein pathway in endothelial cells. Early diagnosis, clinical screening and aggressive management can greatly reduce morbidity and mortality.

Developmental abnormalities and liver disease in childhood

Chapter

Jan 2012

DLL4/Notch1 and BMP9 Interdependent Signaling Induces Human Endothelial Cell Quiescence via P27KIP1 and Thrombospondin-1

Article

Oct 2015
ARTERIOSCL THROM VAS

Objective: Bone morphogenetic protein-9 (BMP9)/activin-like kinase-1 and delta-like 4 (DLL4)/Notch promote endothelial quiescence, and we aim to understand mechanistic interactions between the 2 pathways. We identify new targets that contribute to endothelial quiescence and test whether loss of Dll4(+/-) in adult vasculature alters BMP signaling. Approach and results: Human endothelial cells respond synergistically to BMP9 and DLL4 stimulation, showing complete quiescence and induction of HEY1 and HEY2. Canonical BMP9 signaling via activin-like kinase-1-Smad1/5/9 was disrupted by inhibition of Notch signaling, even in the absence of exogenous DLL4. Similarly, DLL4 activity was suppressed when the basal activin-like kinase-1-Smad1/5/9 pathway was inhibited, showing that these pathways are interdependent. BMP9/DLL4 required induction of P27(KIP1) for quiescence, although multiple factors are involved. To understand these mechanisms, we used proteomics data to identify upregulation of thrombospondin-1, which contributes to the quiescence phenotype. To test whether Dll4 regulates BMP/Smad pathways and endothelial cell phenotype in vivo, we characterized the vasculature of Dll4(+/-) mice, analyzing endothelial cells in the lung, heart, and aorta. Together with changes in endothelial structure and vascular morphogenesis, we found that loss of Dll4 was associated with a significant upregulation of pSmad1/5/9 signaling in lung endothelial cells. Because steady-state endothelial cell proliferation rates were not different in the Dll4(+/-) mice, we propose that the upregulation of pSmad1/5/9 signaling compensates to maintain endothelial cell quiescence in these mice. Conclusions: DLL4/Notch and BMP9/activin-like kinase-1 signaling rely on each other's pathways for full activity. This represents an important mechanism of cross talk that enhances endothelial quiescence and sensitively coordinates cellular responsiveness to soluble and cell-tethered ligands.

Vascular Disorders of the Liver

Article

Dec 2009

Ian Robert Wanless

The genetics of cerebrovascular malformations

Article

Mar 2002
Semin Cerebrovasc Dis Stroke

S Aminhanjani

Certain rare familial or congenital syndromes include cerebrovascular malformations among their constellations of abnormalities. In addition, recognition of familial clustering in a subset of patients with cerebrovascular malformations has led to studies investigating the underlying genetic basic for these lesions. Genetic defects have been identified that cause familial cerebral cavernous malformations and hereditary hemorrhagic telangiectasia, a syndrome that features cerebral arteriovenous malformations. In addition to enhancing presymptomatic screening, identification of the responsible genes may result in a better understanding of the pathogenesis of these lesions, and ultimately, in novel treatments.

Hereditary Hemorrhagic Telangiectasia (HHT) in Dentistry: A Literature Review

Article

Full-text available

Sep 2006
EUR J INFLAMM

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal-dominantly-inherited vascular dysplasia characterized by age-dependant incomplete penetrance and variable expressivity, with clinical manifestations consisting in epistaxis, mucocutaneous telangiectases, gastrointestinal bleeding and arteriovenous malformations (AVMs), which affects approximately 1/2 million people world-wide. It affects males and females of all racial and ethnic groups. Up to 1/3 of HHT patients have multiple organ involvement, which can be disabling and/or life threatening. HHT can be treated successfully if correctly diagnosed. Morbidity of HHT is often due to complications of AVMs, such as stroke or haemorrhage, also known to occur in children. Many authors have reported successful new therapeutical options for AVMs, which have resulted in a significant decrease of life-threatening complications and HHT morbidity. Since early diagnosis permits an appropriate care of affected subjects, a very sensitive mutation screening technique is required to identify the mutation carriers among all at-risk individuals belonging to HHT-families. There may be one or more genes that cause HHT but, if so, they are quite rare. Currently, scientists are trying to better understand exactly how the abnormal gene can interfere with normal blood vessel formation and promote the phenotype of HHT, so that better treatments for the symptoms of HHT can be developed.

Maladie de Rendu-Osler

Article

Jan 2014
REV MED INTERNE

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) is a development disorder of the vasculature characterized by telangiectases and arteriovenous malformations in specific locations. Among monogenic disorders, it is one of the most common, though affected individuals are widely underdiagnosed. The most common features of this disorder, nosebleeds, and telangiectases on the lips, hands, and oral mucosa are often quite subtle. Mutations in at least five genes may result in hereditary hemorrhagic telangiectasia, but mutations in two genes (ENG and ACVRL1/ALK1) account for approximately 85% of cases. Optimal management requires understanding the specific clinical patterns of these vascular malformations, especially their locations and timing during life. Therapeutic modulation of angiogenesis may be an effective therapy. Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Endoglin (CD105): A Strong Candidate for Immunologic Targeting of Tumor Neovasculature in Human Malignancies

Article

Jan 2008

Tumor-associated angiogenesis is a well-acknowledged therapeutic target for human malignancies, and different markers of tumor neovasculature are actively investigated as potential candidates for antiangiogenetic therapy in cancer. Among these is endoglin (CD105), a homodimeric transmembrane glycoprotein overexpressed on proliferating endothelial cells, which has been identified as a functional component of the transforming growth factor-β (TGF-β) receptor system about a decade ago. The large body of experimental data accumulated so far indicates that CD105 plays a crucial role in angiogenesis and vascular integrity; furthermore, intratumoral microvessel density as evaluated by staining for CD105 represents a strong prognostic factor in solid malignancies of different histology. In this work, we review the biologic features of CD105 and the complex of evidences highlighting its great potentialities as novel target for diagnostic and therapeutic approaches in human malignancies.

TGF-β Signaling and Vascular Morphogenesis

Article

Jan 2008

Transforming growth factor-β (TGF-β) is a multifunctional cytokine with pivotal roles in development and tissue homeostasis. TGF-β initiates its cellular responses by signaling via specific type I and type II serine/threonine kinase receptors and downstream Smad effector proteins. In vitro studies with cocultured endothelial and smooth muscle cells, as well as genetic studies in humans and mice, have revealed an important role for TGF-β in vascular development and maintenance. TGF-β not only affects angiogenesis by directly influencing endothelial and mural cell functions, but also by recruiting inflammatory cells, which release cytokines that act on vascular cells. Hereditary Hemorrhagic Telangiectasia (HHT), a dominant vascular disorder, has been linked to mutations in TGF-β type I activin receptor-like kinase 1 (ALK1) and the accessory TGF-β receptor endoglin. Mice deficient for various TGF-β signaling components develop an embryonic lethality due to vascular defects. In this review, we present our current understanding on the role of TGF-β signaling in angiogenesis and vascular disorders.

Manifestations vasculaires pulmonaires de la maladie de Rendu-Osler

Article

Apr 2006
PRESSE MED

IntroductionOsler-Weber-Rendu disease (hereditary hemorrhagic telangiectasia) is an autosomal dominant genetic disorder with variable penetrance. It is estimated to affect at least one in ten thousand of the population in France. The diagnosis is clinical and depends on the association of epistaxis, telan-giectasia, visceral manifestations of the disease, and familial occurrence.State of the artPulmonary arterio-venous malformations (AVM) which occur in about 15-30 % of patients with this condition represent the main visceral complication of the disease. Infectious and ischaemic neurological manifestations due to paradoxical embolism may occur and may be the presenting feature. The high frequency of neurological complications even in asymptomatic patients justifies systematic screening for pulmonary AVMs, using chest radiography, contrast echocardiography, and/or chest CT. Treatment is based on percutaneous transcatheter coil vaso-occlusion of the feeding artery.Conclusion Pulmonary arterial hypertension is rare. It may be due to systemic arteriovenous shunting in the liver increasing cardiac output, or be similar to idiopathic pulmonary hypertension.

[Hereditary hemorrhagic telangiectasia.]

Article

Mar 2013

Transforming growth factor Β family members in regulation of vascular function: In the light of vascular conditional knockouts

Article

Feb 2013
EXP CELL RES

Blood vessels are composed of endothelial cells, mural cells (smooth muscle cells and pericytes) and their shared basement membrane. During embryonic development a multitude of signalling components orchestrate the formation of new vessels. The process is highly dependent on correct dosage, spacing and timing of these signalling molecules. As vessels mature some cascades remain active, albeit at very low levels, and may be reactivated upon demand. Members of the Transforming growth factor β (TGF-β) protein family are strongly engaged in developmental angiogenesis but are also regulators of vascular integrity in the adult. In humans various genetic alterations within this protein family cause vascular disorders, involving disintegration of vascular integrity. Here we summarize and discuss recent data gathered from conditional and endothelial cell specific genetic loss-of-function of members of the TGF-β family in the mouse.

Oxidative Stress Contributes to Endothelial Dysfunction in Mouse Models of Hereditary Hemorrhagic Telangiectasia

Article

Full-text available

Dec 2012
OXID MED CELL LONGEV

Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia caused by mutations in endoglin (ENG; HHT1) or activin receptor-like kinase (ALK1; HHT2) genes, coding for transforming growth factor-β (TGF-β) superfamily receptors. We demonstrated previously that endoglin and ALK1 interact with endothelial NO synthase (eNOS) and affect its activation. Endothelial cells deficient in endoglin or ALK1 proteins show eNOS uncoupling, reduced NO, and increased reactive oxygen species (ROS) production. In this study, we measured NO and H(2)O(2) levels in several organs of adult Eng and Alk1 heterozygous mice, to ascertain whether decreased NO and increased ROS production is a generalized manifestation of HHT. A significant reduction in NO and increase in ROS production were found in several organs, known to be affected in patients. ROS overproduction in mutant mice was attributed to eNOS, as it was L-NAME inhibitable. Mitochondrial ROS contribution, blocked by antimycin, was highest in liver while NADPH oxidase, inhibited by apocynin, was a major source of ROS in the other tissues. However, there was no difference in antimycin- and apocynin-inhibitable ROS production between mutant and control mice. Our results indicate that eNOS-derived ROS contributes to endothelial dysfunction and likely predisposes to disease manifestations in several organs of HHT patients.

Endoglin, a TGF-?? binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1

Article

Full-text available

Dec 1994

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia and recurrent haemorrhage. Linkage for some families has been established to chromosome 9q33-q34. In the present study, endoglin, a transforming growth factor beta (TGF-beta) binding protein, was analysed as a candidate gene for the disorder based on chromosomal location, expression pattern and function. We have identified mutations in three affected individuals: a C to G substitution converting a tyrosine to a termination codon, a 39 base pair deletion and a 2 basepair deletion which creates a premature termination codon. We have identified endoglin as the HHT gene mapping to 9q3 and have established HHT as the first human disease defined by a mutation in a member of the TGF-beta receptor complex.

Rare diseases bullet 4: Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms

Article

Full-text available

Aug 1999
THORAX

Epithelial-mesenchymal transformation of embryonic cardiac endothelial cells is inhibited by a modified antisense oligodeoxynucleotide to transforming growth factor beta 3.

Article

Full-text available

Mar 1991

During early cardiac development, the progenitor cells of the heart valves and membranous septa undergo an epithelial-mesenchymal transformation. Previous studies have shown that this transformation depends on the activity of a transforming growth factor beta (TGF beta) molecule produced by the heart. In the present study, we have used modified antisense oligodeoxynucleotides generated to nonconserved regions of TGF beta 1, -2, -3, and -4 to examine the possible roles of these members in this transformation. A phosphoramidate-modified oligonucleotide complementary to TGF beta 3 mRNA was capable of inhibiting normal epithelial-mesenchymal transformation by 80%. Unmodified oligonucleotides to TGF beta 3, modified oligonucleotides to TGF beta 1, -2, and -4, and two modified control oligonucleotides were unable to inhibit the transformation. These data demonstrate that a specific member of the TGF beta family, TGF beta 3, is essential for the epithelial-mesenchymal cell transformation.

Autoinduction of transforming growth factor ??1 is mediated by the AP-1 complex

Article

Full-text available

May 1990

The multifunctional actions of transforming growth factor beta 1 (TGF-beta 1) indicate that it has a pivotal control function in many physiological and pathological processes. An important property of TGF-beta 1 is its ability to activate its own mRNA expression and thereby increase its own secretion. Two distinct regions of the promoter of the TGF-beta 1 gene are responsive to autoregulation: one 5' to the upstream transcriptional start site and another located between the two major start sites. In both promoter regions, autoinduction is mediated by binding of the AP-1 (Jun-Fos) complex. An important contribution to this positive regulation is the autoactivation of c-jun transcription by AP-1. Cotransfection of antisense c-jun or antisense c-fos expression vectors prevents TGF-beta 1 autoinduction. These results demonstrate that both components of the AP-1 complex are required for TGF-beta 1 autoinduction. Induction of jun expression by TGF-beta 1, as well as jun autoinduction, may amplify the action of TGF-beta 1 during normal development and oncogenesis.

Ultrastructure and Three-Dimensional Organization of the Telangiectases of Hereditary Hemorrhagic Telangiectasia

Article

Full-text available

Nov 1990

We studied 10 cutaneous telangiectatic lesions of hereditary hemorrhagic telangiectasia (HHT), ranging in size from pinpoint to 2 mm, by light and electron microscopy. Four representative lesions were reconstructed by computer from serial 1- or 2-mm plastic embedded sections. The earliest clinically detectable lesion of HHT is a focal dilatation of postcapillary venules, which continue to enlarge and eventually connect with dilated arterioles through capillaries. As the vascular lesion increases in size, the capillary segments disappear and a direct arterio-venous communication is formed. This entire sequence of morphologic events is associated with a perivascular mononuclear cell infiltrate in which the majority of cells are lymphocytes and the minority are monocytes/macrophages by ultrastructure. Comparison of these findings with the telangiectatic mats of scleroderma and cherry angiomas revealed that the former, previously shown to be composed of dilated postcapillary venules, are also associated with perivascular infiltrates, but the latter, which are produced by capillary loop aneurysms, are not.

Single-Step Method Of RNA Isolation By Acid Guanidinium Thiocyanate-Phenol-Chlorform Extraction

Article

Full-text available

May 1987

A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.

Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice

Article

Full-text available

Jul 1995

Transforming growth factor beta 1 (TGF beta 1) is shown here to be required for yolk sac haematopoiesis and endothelial differentiation. Mice with a targeted mutation in the TGF beta 1 gene were examined to determine the cause of prenatal lethality, which occurs in 50% of homozygous TGF beta 1 null (TGF beta 1-/-) conceptions. 50% of TGF beta 1-/- and 25% of TGF beta 1-+-) conceptions. 50% of TGF beta 1-/- and 25% of TGF beta 1+/- conceptuses were found to die at around 10.5 dpc. The primary defects were restricted to extraembryonic tissues, namely the yolk sac vasculature and haematopoietic system. The embryos per se showed developmental retardation, oedema and necrosis, which were probably secondary to the extraembryonic lesions. The defect in vasculogenesis appeared to affect endothelial differentiation, rather than the initial appearance and outgrowth of endothelial cells. Initial differentiation of yolk sac mesoderm to endothelial cells occurred, but defective differentiation resulted in inadequate capillary tube formation, and weak vessels with reduced cellular adhesiveness. Defective haematopoiesis resulted in a reduced erythroid cell number within the yolk sac. Defective yolk sac vasculogenesis and haematopoiesis were present either together, or in isolation of each other. The phenotypes are consistent with the observation of abundant TGF beta 1 gene expression in both endothelial and haematopoietic precursors. The data indicate that the primary effect of loss of TGF beta 1 function in vivo is not increased haematopoietic or endothelial cell proliferation, which might have been expected by deletion of a negative growth regulator, but defective haematopoiesis and endothelial differentiation.

Antibodies to the Type II TGFβ Receptor Block Cell Activation and Migration during Atrioventricular Cushion Transformation in the Heart

Article

Full-text available

Apr 1996

Epithelial-mesenchymal transformation is a critical event in the development of many organ systems including the heart. Descriptive studies have implicated a number of factors in mediating this transformation, including transforming growth factor beta (TGFbeta). We now report that disruption of a TGFbeta signal transduction complex by antibodies directed against the Type II TGFbeta receptor blocks both the endocardial cell activation and subsequent migration that constitute transformation in the chick atrioventricular (AV) cushion. The Type II receptor was localized to both endothelial and endocardial cells of the chick embryo. Incubation of AV cushion explants from Stage 14, 16, and 18 embryos with antibody resulted in a blockade of AV endocardial cell transformation by greater than 50% as measured by mesenchyme formation. Similarly, the appearance of procollagen Type I, a marker of endocardial cell transformation, was blocked. In addition, within 2 hr after the incubation of activated Stage 18 explants with Type II antibody the rate of migration of transformed cells was decreased by 50%. These data suggest that TGFbeta acts directly on AV cushion endocardial cells to stimulate epithelial-mesenchymal transformation and that TGFbeta mediates at least two distinct components of AV cushion transformation, activation and migration.

Endoglin modulates cellular responses to TGF-βI

Article

Full-text available

Jul 1996

Endoglin is a homodimeric membrane glycoprotein which can bind the beta 1 and beta 3 isoforms of transforming growth factor-beta (TGF-beta). We reported previously that endoglin is upregulated during monocyte differentiation. We have now observed that TGF-beta itself can stimulate the expression of endoglin in cultured human monocytes and in the U-937 monocytic line. To study the functional role of endoglin, stable transfectants of U-937 cells were generated which overexpress L- or S- endoglin isoforms, differing in their cytoplasmic domain. Inhibition of cellular proliferation and downregulation of c-myc mRNA which are normally induced by TGF-beta 1 in U-937 cells were totally abrogated in L-endoglin transfectants and much reduced in the S-endoglin transfectants. Inhibition of proliferation by TGF-beta 2 was not altered in the transfectants, in agreement with the isoform specificity of endoglin. Additional responses of U-937 cells to TGF-beta 1, including stimulation of fibronectin synthesis, cellular adhesion, platelet/endothelial cell adhesion molecule 1 (PECAM-1) phosphorylation, and homotypic aggregation were also inhibited in the endoglin transfectants. However, modulation of integrin and PECAM-1 levels and stimulation of mRNA levels for TGF-beta 1 and its receptors R-I, R-II, and betaglycan occurred normally in the endoglin transfectants. No changes in total ligand binding were observed in L-endoglin transfectants relative to mock, while a 1.5-fold increase was seen in S-endoglin transfectants. The degradation rate of the ligand was the same in all transfectants. Elucidating the mechanism by which endoglin modulates several cellular responses to TGF-beta 1 without interfering with ligand binding or degradation should increase our understanding of the complex pathways which mediate the effects of this factor.

The liver in hereditary hemorrhagic telangiectasia (Weber-Rendu-Osler disease)

Article

Feb 2000

Background: Hereditary hemorrhagic telangiectasia (HHT, Osler disease) is an inborn error in the structure of different vessels. This leads to vascular malformations in multiple organ systems. In the liver vascular abnormalities are associated with a marked fibrosis and/or cirrhosis. Methods and results: We found hepatic manifestation of Osler disease in four women and one man (51-63 years old) presenting initially with slight disturbances of liver function. In three patients progressive liver insufficiency developed. The characteristic histologic and sonographic findings are described and discussed. Conclusion: Ultrasonography with color and Doppler analysis is diagnostic, replacing more extensive procedures like angiography, computer tomography, or magnetic resonance tomography.

Defective Angiogenesis in Mice Lacking Endoglin

Article

May 1999

Dean Y. Li

Endoglin is a transforming growth factor–β (TGF-β) binding protein expressed on the surface of endothelial cells. Loss-of-function mutations in the human endoglin gene ENGcause hereditary hemorrhagic telangiectasia (HHT1), a disease characterized by vascular malformations. Here it is shown that by gestational day 11.5, mice lacking endoglin die from defective vascular development. However, in contrast to mice lacking TGF-β, vasculogenesis was unaffected. Loss of endoglin caused poor vascular smooth muscle development and arrested endothelial remodeling. These results demonstrate that endoglin is essential for angiogenesis and suggest a pathogenic mechanism for HHT1.

Endoglin modulates cellular responses to TGF-beta 1

Article

Jun 1996

Pedro Lastres

The Liver in Hereditary Hemorrhagic Telangiectasia (Weber-Rendu-Osler Disease)

Article

Jan 1999

Lucas Greiner

Background: Hereditary hemorrhagic telangiectasia (HHT, Osler disease) is an inborn error in the structure of different vessels. This leads to vascular malformations in multiple organ systems. In the liver vascular abnormalities are associated with a marked fibrosis and/or cirrhosis. Methods and Results: We found hepatic manifestation of Osler disease in four women and one man (51-63 years old) presenting initially with slight disturbances of liver function. In three patients progressive liver insufficiency developed. The characteristic histologic and sonographic findings are described and discussed. Conclusion: Ultrasonography with color and Doppler analysis is diagnostic, replacing more extensive procedures like angiography, computer tomography, or magnetic resonance tomography.

Abdalla SA, Pece-Barbara N, Vera S, Tapia E, Paez E, Bernabeu C, Letarte M. Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2

Article

May 2000
HUM MOL GENET

Stella Crescenti Abdalla

ALK-1 (activin receptor-like kinase-1), a type I receptor of the transforming growth factor (TGF)-β superfamily, is the gene mutated in hereditary hemorrhagic telangiectasia type 2 (HHT2) while endoglin is mutated in HHT1. Using a novel polyclonal antibody to ALK-1, we measured ALK-1 expression on human umbilical vein endothelial cells (HUVEC) of newborns from HHT families whose affected members had normal endoglin levels. ALK-1 levels were specifically reduced in three HUVEC with ALK-1 missense mutant codons, and normal in two newborns not carrying the missense mutations present in the clinically affected relatives. Levels were also normal in a HUVEC with deletion of S232 in the ATP binding site of ALK-1. Thus HHT2 appears to be associated with a loss of function of the mutant allele due to a reduction in either protein level or activity. We also report three new ALK-1 missense mutations leading to G48E/A49P, C344Y and E407D substitutions. In COS-1 transfected cells, ALK-1 was found in the TGF-β1 and -β3 receptor complexes in association with endoglin and TβRII, but not in activin receptor complexes containing endoglin. In HUVEC, ALK-1 was not detectable in the TGF-β1 or -β3 receptor complexes. However, in the absence of ligand, ALK-1 and endoglin interactions were observed by immunoprecipitation/western blot in HUVEC from normal as well as HHT1 and HHT2 patients. Our data suggest a transient association between these two proteins of the TGF-β superfamily, both required at a critical level to ensure vessel wall integrity.

Interactions of Vascular Cells with Transforming Growth Factors?

Article

Jun 1990

CELL BIOLOGY: Signaling Vascular Morphogenesis and Maintenance

Article

Jul 1997

Douglas Hanahan

[ Douglas Hanahan ][1] Blood vessels are formed and maintained by a family of soluble factors that interact with tyrosine kinase receptors on the endothelial cell surface. A new angiogenesis factor (Ang2) is reported in an article by [ Maisonpierre et al .][2] in this week's issue. Hanahan describes what is known about the process of vascular morphogenesis and maintenance and how this new factor fits into this complex regulatory system. [][3] [1]: http://www.sciencemag.org#affiliation [2]: http://www.sciencemag.org/cgi/content/short/277/5322/55 [3]: http://

Identification of Hereditary Hemorrhagic Telangiectasia Type 1 in Newborns by Protein Expression and Mutation Analysis of Endoglin

Article

Jan 2000

Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited vascular disorder that is heterogeneous in terms of age of onset and clinical manifestations, Endoglin is the gene mutated in HHT1, which is associated with a higher prevalence of pulmonary arteriovenous malformations than HHT2, where ALK-1 is the mutated gene. Endoglin is constitutively expressed on endothelial cells and inducible on peripheral blood activated monocytes so that protein levels can be measured by metabolic labeling and immunoprecipitation. We report the analysis of umbilical vein endothelial cells in 28 newborns from 24 families with a clinical diagnosis of HHT. Reduced levels of endoglin were observed in umbilical vein endothelial cells in 15/28 subjects and in activated monocytes of all clinically affected relatives tested, suggesting that these individuals had HHT1. No mutant protein was expressed at the cell surface in any of these cases, and a transient intracellular species was seen in samples of only two families, supporting a haploinsufficiency model. Quantitative multiplex PCR fragment analysis was established for the endoglin gene and revealed six mutations that were confirmed by automated DNA sequencing. An additional 10 mutations were identified in newborns by sequencing all exons. Of the 16 mutations, 10 were novel, three had been independently identified in related families, and three were previously known. Our data confirm that endoglin levels correlate with the presence or absence of mutation in HHT1 families, allowing the early identification of affected newborns that should be screened clinically to avoid serious complications of this disorder, such as cerebral arteriovenous malformations.

TGF-?? Receptor Type II Deficiency Results in Defects of Yolk Sac Hematopoiesis and Vasculogenesis

Article

Nov 1996

TGF-β signaling is mediated through two types of serine/threonin kinase-containing receptors, type I (TGF-βRI) and type II (TGF-βRII), which form a heteromeric complex. In this signaling complex, ligand binding TGF-βRII phosphorylates and thereby activates the TGF-βRI to signal downstream pathways. To determine the role of TGF-βRII in embryogenesis, we have generated a TGF-βRII gene (Tgfbr2) knockout mouse line. The heterozygousTgfbr2knockout mice are developmentally normal. The homozygousTgfbr2mutation causes defects in the yolk sac hematopoiesis and vasculogenesis, resulting in an embryonic lethality around 10.5 days of gestation. This phenotype is indistinguishable from the previously reported embryonic lethality by the homozygous TGF-β1 gene (Tgfb1) null mutation. In addition, we have generated chimeric mice using aTgfbr2(−/−) embryonic stem cell line. Some chimeric mice showed several types of congenital anomalies, suggesting that TGF-βRII is important for normal development in a variety of organs.

Molecular and functional aspects of PECAM-1/CD31

Article

Nov 1994
Immunol Today

Among vascular cell adhesion molecules, platelet-endothelial cell adhesion molecule (PECAM-1/CD31) has the distinctive feature of being expressed on several of the major cell types associated with the vascular compartment. This makes it uniquely positioned to mediate multiple and important cell-cell interactions involving platelets, leukocytes and endothelial cells. Thus, PECAM-1 may represent a potential target for new therapeutic agents directed at a variety of pathological states.

The TGF-?? family and its cognate receptors

Article

May 1994
TRENDS CELL BIOL

In their search for regulators of animal growth and development, biologists have often come upon members of the transforming growth factor β(TGF-β) family and have realized that these are among the most versatile carriers of growth and differentiation signals. New evidence suggests that these factors signal through receptors with remarkable structures. Each receptor is a complex of two distantly related transmembrane serine/threonine kinases that are both essential for signalling. TGF-β and related factors have at their disposal a repertoire of such receptors, a feature that could account for their multifunctional nature.

Molecular and Cell Biology of TGF-β

Article

Feb 1998

Anita B. Roberts

The TGF-betas are a remarkable set of peptides consisting of three highly homologous isoforms, TGF-beta 1, 2, and 3. Distinguished initially for their ability to inhibit the growth of most epithelial and hematopoietic cells and to regulate the production of extracellular matrix by mesenchymal cells, these peptides are now known to act via autocrine, paracrine, and endocrine modes to control a wide variety of developmental processes and to play key roles in the pathogenesis of many diseases including especially fibrotic diseases, parasitic diseases, autoimmune diseases, and carcinogenesis. The activity of these peptides is under tight control by processes including regulation of the expression of the isoforms and their receptors and of the trafficking and activation of their latent forms.

Hereditary hemorrhagic telangiectasia.

Article

May 1946
AM J MED SCI

E B WELLS

The liver in hereditary haemorrhagic teleangiectasia: An inborn error of vascular structure with multiple manifestations: A reappraisal

Article

Jul 1978

G A Martini

Hereditary haemorrhagic teleangiectasia (Rendu-Osler-Weber disease) is an inborn error of vascular structure with multiple manifestations. Its incidence is about 1-2:100 000 in the European population. The incidence of telangiectases and/or fistula formation was estimated to be 1 in 10 carriers of the Osler trait. The findings in the family reported herewith suggest a much higher incidence if angiography is more frequently performed. Apart from the skin and mucous membrane, teleangiectases and/or arteriovenous fistulas may be present in the lungs, intestinal tract, spleen, kidney, brain, and bones. The liver apparently is more involved than was orginally suspected. The vascular derangement includes teleangiectases, arteriovenous fistulas, and connective tissue formation with fibrosis and atypical cirrhosis. In intestinal bleeding laser coagulation seems to be very efficient. The pathogenesis of teleangiectases is not known but involves several factors such as special formation of venules, capillaries and arterioles, abnormal perivascular connective tissue and endothelial cells.

The liver in hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease)

Article

Jun 1976
AM J MED

The livers of four patients with hereditary hemorrhagic telangiectasia--including the original case of Osler--were examined at autopsy. Characteristic random focal fibrovascular lesions were found in all. The importance of recognizing the apparently common and seemingly benign hepatic involvement in this disease is emphasized in view of its possible confusion with more serious types of liver disease that may complicate the condition.

Hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)

Article

Sep 1975
J Indian Med Assoc

TGF-?3-Mediated tissue interaction during embryonic heart development

Article

Jun 1992

A critical process during early heart development is the formation of mesenchymal cells which will contribute to valves and septa of the mature heart. These cells arise by an epithelial-mesenchymal transformation of endothelial cells in the atrioventricular (AV) canal and outflow tract areas of the heart. Adjacent endothelial cells in the atrium and ventricle remain epithelial. A three-dimensional collagen gel culture system has been exploited to examine the interactions that mediate this transformation. The AV canal myocardium produces a stimulus that is transmitted through an intervening extracellular matrix to the AV canal endothelium. This interaction is regionally specific, such that ventricular myocardium does not provide an adequate stimulus and ventricular endothelium does not respond to the AV canal myocardial stimulus. Exogenous TGF-beta 1 (or TGF-beta 2) can complement ventricular myocardium to produce transformation by AV canal endothelium. A blocking antibody, effective against several TGF-beta, prevents cell transformation. To identify the specific member of the TGF-beta family that functions in situ, antisense oligonucleotides for each of the numbered TGF-beta were topically added to AV canal explant cultures. Only the oligonucleotide targeted to TGF-beta 3 was an effective inhibitor of mesenchymal cell formation. Studies have been undertaken to localize specific mRNas by in situ hybridization and RNase protection assays. These assays have concentrated on the regional and temporal appearance of TGF-beta 2 and 3. Surprisingly, RNase protection assays with a TGF-beta 3 sense probe showed the presence of a transcript complementary to TGF-beta 3.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of TGF-?s in mammalian development and neoplasia

Article

Jun 1992

To date, three mammalian TGF-β isoforms have been identified, each encoded by different genetic loci. Through each is very similar in primary amino acid structure, there are clear differences both in the mature bioactive peptide region and in the latency-associated peptide, which could potentially confer differential biological specificity. As one route to investigate differential biological function in vivo we have used gene specific probes for in situ hybridization studies to examine the distribution of RNA transcripts during mammalian embryogenesis. Mouse embryos from 6 to 14.5 gestational age and human embryos from 32 to 57 days post-fertilization have been probed. A general conclusion from these studies is that each TGFβ gene has a distinct, through overlapping, pattern of transcript distribution and that this pattern, in most cases, is conserved between mouse and man. We have focused on the biological function the TGF-betas play in certain epithelia and in cardiogenesis, which will be discussed in this presentation.

Expression cloning and characterization of the TGF-beta type III receptor

Article

Dec 1991
CELL

The rat TGF-beta type III receptor cDNA has been cloned by overexpression in COS cells. The encoded receptor is an 853 amino acid protein with a large N-terminal extracellular domain containing at least one site for glycosaminoglycan addition, a single hydrophobic transmembrane domain, and a 41 amino acid cytoplasmic tail with no obvious signaling motif. Introduction of the cDNA into COS cells and L6 myoblasts induces expression of a heterogenously glycosylated 280-330 kd protein characteristic of the type III receptor that binds TGF-beta 1 specifically. In L6 myoblasts lacking the endogenous type III receptor, expression of the recombinant receptor leads to an increase in the amount of ligand bound and cross-linked to surface type II TGF-beta receptors. This indicates that the type III receptor may regulate the ligand-binding ability or surface expression of the type II receptor.

Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-?? receptor system

Article

Dec 1991
CELL

We describe the primary structure of rat betaglycan, a polymorphic membrane-anchored proteoglycan with high affinity for transforming growth factor-beta (TGF-beta). As deduced from its cDNA sequence, the 853 amino acid core protein of betaglycan has an extracellular domain with clustered sites for potential attachment of glycosaminoglycan chains. These chains are dispensable for TGF-beta binding to the core protein. The transmembrane region and the short cytoplasmic tail of betaglycan are very similar to these regions in human endoglin, an endothelial cell membrane glycoprotein involved in intercellular recognition. The ectodomain of betaglycan can be released as a soluble proteoglycan; a potential cleavage site near the transmembrane region is identical to the highly regulated cleavage site of the membrane-anchored transforming growth factor-alpha precursor. The unique features of betaglycan suggest important roles in cell interaction with TGF-beta.

PECAM-1 (CD31) Cloning and Relation to Adhesion Molecules of the Immunoglobulin Gene Superfamily

Article

Apr 1990

An antibody to a platelet integral membrane glycoprotein was found to cross-react with the previously identified CD31 myelomonocytic differentiation antigen and with hec7, an endothelial cell protein that is enriched at intercellular junctions. This antibody identified a complementary DNA clone from an endothelial cell library. The 130-kilodalton translated sequence contained six extracellular immunoglobulin (Ig)-like domains and was most similar to the cell adhesion molecule (CAM) subgroup of the Ig superfamily. This is the only known member of the CAM family on platelets. Its cell surface distribution suggests participation in cellular recognition events.

[Rendu Osler disease revealed by ruptured cerebral arterial aneurysm in an infant]

Article

Jan 1991

A 6 week-old boy whose mother and sister present with hereditary hemorrhagic telangiectasia (HHT) presented suddenly with listlessness, hypotonia, and acute anemia. Cerebrospinal fluid was grossly hemorrhagic. Brain CT scan was compatible with subarachnoid and intracerebral hemorrhage. Operative investigation diagnosed a ruptured aneurysm of one branch of the right middle cerebral artery. A large clot was removed from the right frontal lobe. The ruptured artery was clipped. Further cerebral and abdominal angiographies did not show other aneurysms. The infant died 18 days later, with bilateral subdural hematoma. The family history and review of the literature suggest that the rupture of a cerebral aneurysm in this infant may have been an early manifestation of HHT. Brain CT scan study seems mandatory in every infant born to a mother with HHT.

Characterization of a novel myeloid antigen regulated during differentiation of monocyte cells

Article

Aug 1989

The monoclonal antibody HC1/6 generated against phorbol 12-myristate 13-acetate-treated U-937 cells recognizes a new cell surface antigen with a broad relative molecular mass ranging from 100 to 150 kDa. This antigen is also present on monocytes, platelets and endothelial cells and is weakly expressed by granulocytes. In contrast, it is absent from T, B and erythroblastoid cells. The antigen HC1/6 is also expressed by normal tissue macrophages in tonsil, lung and kidney, as well as in skin biopsies from pathologies such as sarcoidosis and lepromatous leprosy. The expression of the HC1/6 antigen is increased up to 5-fold when U-937 (promonocytic) and HL-60 (myelomonocytic) cell lines are stimulated with phorbol 12-myristate 13-acetate. Conversely, the expression of the HC1/6 antigen is down-regulated in monocytes upon treatment with interferon-gamma. These findings are discussed in relation with other myeloid cell surface markers.

Portal shunting and resistance to Schistosoma mansoni in 129 strain mice

Article

Jan 1990

The integrity of the hepatic portal vasculature was examined, relative to the resistance to Schistosoma mansoni observed in 68% of 129/Ola mice. The passage of microspheres to the lungs, following their injection via the superior mesenteric vein, indicated the presence of shunts in the majority of both naive and infected mice. There was a negative association between shunting of microspheres to the lungs and paucity of liver worms at 28/35 days post-infection. Schistosomula accumulated in the livers of resistant mice at a slower rate than in susceptible animals, and after day 21 relocated to the lungs. Many lung schistosomula injected via the superior mesenteric passed immediately to the lungs; the shunts thus greatly reduce the probability of trapping in the liver. Some parasites migrated back from the lungs, successfully lodged in the liver and began to feed on blood. Latex infusion demonstrated the location of large intrahepatic connections between the portal and hepatic veins. We suggest that as these liver worms grow, migrating upstream into progressively larger vessels, they reach the connections, pass out of the hepatic portal system, and relocate to the lungs. The presence of the natural shunts thus accounts for the resistant status of the mice.

Schistosoma mansoni: Evidence that vascular abnormalities correlate with the 'non-permissive' trait in 129/Ola mice

Article

Jan 1990

The pulmonary and portal vasculature of naïve mice of the 129/Ola and CBA/Ca strains has been studied by means of the vasculature casting technique. This involve injection of pigmented vinylite resin into the arterial and venous systems, followed by digestion of the tissues with KOH. The peripheral vessels of the arterial and portal systems of CBA/Ca mice were numerous and highly branched. In contrast, casts prepared from 70-80% of naïve 129/Ola mice showed dramatic reductions in the number and extent of the peripheral vessels. In addition, such vessels appeared severely truncated. The remaining 20-30% of naïve 129/Ola mice yielded lung and liver casts that were indistinguishable from the CBA/Ca casts. Casts prepared from 129/Ola mice infected 6 weeks previously with Schistosoma mansoni cercariae showed the same segregation; faecal smears, together with observations of presence or absence of gross pathology in such mice confirmed that the vascular changes correlated with the 'non-permissive trait'. We propose that such alterations facilitate the reportedly abnormal migration of schistosomes from the liver to the lungs in 'non-permissive' 129/Ola mice.

Article

Mar 1989

We report the results of a comprehensive and systematic clinical study of 324 patients with hereditary hemorrhagic telangiectasia, selected from a total of 1,270 cases recruited by epidemiological survey. In 94% of the cases, familial occurrence suggested autosomal dominant inheritance; maximum penetrance for at least one manifestation was 97%. Epistaxis was reported by 96% of the patients and, in more than 50%, developed before age 20. Heavy and frequent bleeding occurred mainly in middle-aged patients. Telangiectasia was documented in 74% of cases, half of whom were younger than 30 years. The frequency of involvement of the hands and wrists was 41%, and for the face, 33%. Visceral involvement was present in 25% of patients, with affected lungs and CNS in the young and gastrointestinal tract and liver in older patients. Symptomatic urinary tract involvement was seen in only two/324 patients. Involvement of other internal sites was not observed.

Gastrointestinal Lesions in Hereditary Hemorrhagic Telangiectasia

Article

Dec 1986
GASTROENTEROLOGY

Gastrointestinal bleeding is the most frequent form of bleeding after epistaxis in patients with hereditary hemorrhagic telangiectasia. As a part of an epidemiologic study, gastrointestinal telangiectases could be endoscopically demonstrated in 28 patients with hereditary hemorrhagic telangiectasia, most frequently in the upper gastrointestinal tract and predominantly in the stomach and the duodenum. The typical endoscopic finding was nodular angiomas that did not differ, with regard to form and size, from external telangiectases. However, in 15 patients some of the gastrointestinal telangiectases were surrounded by an anemic halo. A significant difference was found in the age at onset of epistaxis (median 11 yr) and of gastrointestinal bleeding (median 55.5 yr). There was no intrafamilial or interfamilial variation as to heredity and clinical manifestations. The blood group distribution in patients with hereditary hemorrhagic telangiectasia and gastrointestinal telangiectases did not differ from that of other patients with hereditary hemorrhagic telangiectasia, whereas there was a significantly higher frequency of blood group O among patients with hereditary hemorrhagic telangiectasia than among the background population.

Nodular transformation of the liver in hereditary hemorrhagic telangiectasia

Article

May 1986

A case of hereditary hemorrhagic telangiectasia with prominent nodular transformation of the liver is described. The presence of enlarged arteries was documented morphometrically. Artery-to-portal vein shunts were also found. The association of abnormal vessels with hepatic nodules supports the hypothesis that abnormalities of blood flow cause nodular transformation. Nodular transformation may be the lesion that has heretofore been termed cirrhosis hepatis telangiectasia or atypical cirrhosis.

Subarachnoid hemorrhage in a patient with hereditary hemorrhagic telangiectasia

Article

Aug 1967

Hereditary Hemorrhagic Telangiectasia

Article

Nov 1995

Hereditary hemorrhagic telangiectasia is a rare autosomal dorminant disease that features abnormal and fragile vascular dilations of terminal vessels in skin and mucous membranes, as well as arteriovenous malformations of internal organs, particularly lungs, brain, and liver. Often patients have not been diagnosed with HHT for a long time, and undiagnosed HHT patients unnecessarily develop serious complications such as severe life-threatening hemorrhage, stroke or brain abscess. Therefore, early detection and appropriate screening is very important. Early detection of HHT allows the appropriate screening for the presence of silent disease such as AVMs in the lungs, liver, or brain, and preventive treatment in the patient and their affected family members. Dentists should be familiar with HHT because the telangiectases on skin and oral mucosa are often the most dramatic and most easily identified component of HHT. Recently, we experienced a case of HHT. We present the case with a review of the literature.

Pepper MS, Vassalli JD, Orci L, Montesano R: Biphasic effect of transforming growth factor-beta 1 on in vitro angiogenesis. Exp Cell Res 204: 356-63

Article

Mar 1993

Although the existence of an increasing number of angiogenesis-regulating cytokines is well documented, the response elicited by combinations of these cytokines is largely unknown. Using an in vitro model in which microvascular endothelial cells can be induced to form capillary-like tubes within three-dimensional collagen or fibrin gels, we have investigated the effect of transforming growth factor-beta 1 (TGF-beta 1) on basic fibroblast growth factor (bFGF)-induced and vascular endothelial growth factor (VEGF)-induced angiogenesis. Endothelial cell invasion and capillary lumen formation were inhibited by TGF-beta 1 at relatively high concentrations (5-10 ng/ml), while lower concentrations (100 pg/ml-1 ng/ml) of TGF-beta 1 potentiated the effect of bFGF- and VEGF-induced invasion. The optimal potentiating effect was observed at 200-500 pg/ml TGF-beta 1. At invasion-potentiating doses of TGF-beta 1, lumen size in fibrin gels was markedly reduced compared to that in cultures treated with bFGF alone. These results show that TGF-beta 1 exerts a biphasic effect on bFGF- and VEGF-induced angiogenesis in vitro. Our studies support the notion that the nature of the angiogenic response elicited by a specific cytokine is contextual, i.e., depends on the presence and concentration of other cytokines in the pericellular environment of the responding endothelial cell.

Monstrous Ascites in Hereditary Haemorrhagic Telangiectasia

Article

Feb 1995

Hepatic involvement in hereditary haemorrhagic telangiectasia (HHT) consisting of fibrosis, telangiectases, and cirrhosis, has been reported as a relatively frequent finding. A 50-year-old man with HHT presented with monstrous ascites. Liver biopsy demonstrated multiple dilated sinusoids but not cirrhosis. There were no findings indicative of portal hypertension or malignant disease. Portal pressure, recorded in hepatic vein wedge position, was normal. Arteriography showed numerous hypervascular lesions throughout the liver. The clinical course has been stable for more than 2 years. No other reason for the monstrous ascites could be found. We thus hypothesize that this case of monstrous ascites is due to hepatic involvement in HHT, presenting as numerous vascular lesions throughout the liver.

Expression of TGF-??s and Their Receptors during Implantation and Organogenesis of the Mouse Embryo

Article

Jan 1995

The spatial and temporal expression of the transforming growth factor beta (TGF-beta) receptors type III, type II, and two types I (ALK-5 and Tsk 7L) and their ligands TGF-beta 1 and TGF-beta 2 in postimplantation mouse development were examined using the reverse transcription polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemistry. With RT-PCR, expression of the signaling TGF-beta receptors (types II and ALK-5) was shown to be absent in isolated germ layers of 6.0-7.5 days postcoitum (dpc) embryos, whereas the type III receptor and Tsk 7L were differentially expressed at these stages. In contrast, all TGF-beta receptor types were expressed at these stages in the pregnant uterus and decidua. TGF-beta 1 and TGF-beta 2 transcripts were detected before gastrulation at 6.5 dpc only in the visceral embryonic endoderm, whereas during gastrulation, at 7.5 dpc TGF-beta 1 and TGF-beta 2 mRNA was detected in all three germ layers. In situ hybridization and immunohistochemistry of the expression of the TGF-beta type II receptor confirmed the data obtained by RT-PCR. Furthermore, the type II receptor was detected in the extraembryonic ectoderm of 7.5 dpc embryos. In the embryo proper, TGF-beta type II receptor expression was detected only later in differentiating tissues and developing organs, but not in the brain and neural tube. Since the expression of the type II receptor may essentially determine whether a cell is able to respond to TGF-beta, the results are consistent with the view that TGF-beta s might be implicated in embryo implantation and organogenesis, but are not involved in gastrulation of the embryo.

Central nervous system arteriovenous malformations with hereditary hemorrhagic telangiectasia: Report of a family with three cases

Article

Oct 1994
SURG NEUROL

A family with central nervous system (CNS) arteriovenous malformations (AVMs) and hereditary hemorrhagic telangiectasia (HHT) is reported. A 46-year-old man had an intracerebral hemorrhage. Cerebral angiography showed one AVM and two angiomas. The HHT was diagnosed because of the concomitant existence of cutaneous telangiectasia. The patient's brother had HHT and paraplegia since the age of 21. Magnetic resonance imaging revealed an old spinal cord hemorrhage. The patient's son with HHT had an intracerebral hemorrhage at age 6. Angiograms showed two AVMs and one angioma. Familial CNS AVMs with HHT are extremely rare. The loci for human leukocyte antigen of the affected cases with HHT were evaluated, and the management of CNS AVMs with HHT is discussed.

Vascular malformations of the brain in hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease)

Article

Jun 1994
SURG NEUROL

Six patients with vascular malformation of the brain in hereditary hemorrhagic telangiectasia (HHT) were reviewed to determine clinical and radiographic characteristics of these lesions. There were two patients with arteriovenous fistula (AVF), three with arteriovenous malformation (AVM), and one with multiple AVMs associated with AVF. Seizures were the most common presenting symptom (seen in three patients), and two of them had intracerebral hematomas (ICH). In the remainder, the malformations were incidentally found in the course of evaluation of other diseases. Their locations were variable, but the majority was superficially confined to the cerebral cortex. Arterial supply was from mostly one feeding artery that was a cortical branch of either anterior, middle, or posterior cerebral artery. In six of nine malformations, the venous drainage was through a superficial cerebral vein into either the superior sagittal sinus or transverse sinus. Direct surgery was done on two patients with ICH, artificial embolization on one, and stereotactic radiosurgery on one. The cerebral vascular malformations in HHT are not infrequent, and in particular the importance of computed tomography and cerebral angiography should be recognized in patients with pulmonary AVF associated with HHT.

Mechanism of activation of the TGF-B receptor

Article

Sep 1994

Transforming growth factor-beta (TGF-beta) signals by contacting two distantly related transmembrane serine/threonine kinases called receptors I and II. The role of these molecules in signalling has now been determined. TGF-beta binds directly to receptor II, which is a constitutively active kinase. Bound TGF-beta is then recognized by receptor I which is recruited into the complex and becomes phosphorylated by receptor II. Phosphorylation allows receptor I to propagate the signal to downstream substrates. This provides a mechanism by which a cytokine can generate the first step of a signalling cascade.

Transforming Growth Factor ?? Localization and Role in Surface Epithelium of Normal Human Ovaries and in Ovarian Carcinoma Cells

Article

May 1994

Transforming growth factor alpha (TGF alpha) has been localized by immunohistochemistry in the ovarian surface epithelial (OSE) cells of sections from normal human ovaries and in epithelial cells of surface crypts. An ovarian cancer cell line (HEY) derived from the surface epithelium of a human ovary also exhibited intense staining for the TGF alpha peptide. Using Northern analysis, HEY cells were shown to express a 4.5-kb transcript of TGF alpha, indicating that the TGF alpha peptide was synthesized by these cells and not taken up from the serum in the culture medium and sequestered by the cells. This was confirmed using a radioimmunoassay, which showed that HEY cells in culture secrete TGF alpha peptide, both as a soluble (0.12 +/- 0.02 ng/mg protein) and as a membrane-anchored (0.06 +/- 0.006 ng/mg protein) form. In both normal OSE cells and HEY cells, TGF alpha acted as a growth promoter: TGF alpha significantly stimulated [3H]thymidine incorporation into DNA of both primary cultures of normal OSE cells (2.7-fold) and of HEY cells (2-fold). This study provides the first demonstration of TGF alpha immunostaining in normal surface epithelial cells and in HEY cells, and suggests that TGF alpha, localized in normal and transformed OSE, is an autocrine growth promoter for these cells.

Betaglycan presents ligand to the TGF?? signaling receptor

Article

Aug 1993
CELL

Transforming growth factor beta (TGF beta) signals through a heteromeric protein kinase receptor that has a limited ability to bind ligand. This limitation is overcome by the action of betaglycan (TGF beta type III receptor), a separate TGF beta-binding membrane protein of previously unknown function. Betaglycan presents TGF beta directly to the kinase subunit of the signaling receptor, forming a high affinity ternary complex. Membrane betaglycan increases TGF beta binding to the signaling receptor, enhances cell responsiveness to TGF beta, and eliminates marked biological differences between TGF beta isoforms. Thus, betaglycan is a direct regulator of TGF beta access to the signaling receptors.

Medical complications of pregnancy in hereditary hemorrhagic telangiectasia

Article

Jan 1996

Hereditary haemorrhagic telangiectasia (HHT) displays significant variation in severity between affected individuals in the same family, ranging from relatively trivial epistaxis and telangiectasia to gastrointestinal, cerebral and pulmonary involvement. Evidence for successful therapy of HHT-related haemorrhage with oestrogens and progesterones, and recent case reports outlining pulmonary complications of pregnancy in HHT, prompted us to review the outcome of 161 pregnancies in 47 affected women. HHT-related maternal complications developed in eleven patients, ten in the subgroup of 23 pregnancies in which pulmonary arteriovenous malformations (PAVMs) were present at the outset, or documented in the two years following pregnancy. We present six cases of intrapulmonary shunt deterioration, two cases of fatal pulmonary haemorrhage and three cerebrovascular accidents related to pregnancy. A predisposition towards PAVMs in females was observed. Following the recent discovery of mutations in the endoglin gene in this disease, our data support a hypothesis of hormonal modification of the HHT phenotype. In addition, a significant excess of affected offspring are present in HHT families. We consider contributary aetiological factors, and discuss implications for patient management.

Six novel mutations in the endoglin gene in hereditary hemorrhagic telangiectasia type I suggest a dominant-negative effect of receptor function

Article

Nov 1995

Mutations in the activin receptor–like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2

Article

Jul 1996

Hereditary haemorrhagic telangiectasia, or Osler-Rendu-Weber (ORW) syndrome, is an autosomal dominant vascular dysplasia. So far, two loci have been demonstrated for ORW. Linkage studies established an ORW locus at chromosome 9q3; endoglin was subsequently identified as the ORW1 gene. A second locus, designated ORW2, was mapped to chromosome 12. Here we report a new 4 cM interval for ORW2 that does not overlap with any previously defined. A 1.38-Mb YAC contig spans the entire interval. It includes the activin receptor like kinase 1 gene (ACVRLK1 or ALK1), a member of the serine-threonine kinase receptor family expressed in endothelium. We report three mutations in the coding sequence of the ALK1 gene in those families which show linkage of the ORW phenotype to chromosome 12. Our data suggest a critical role for ALK1 in the control of blood vessel development or repair.

Potential Role of Modifier Genes Influencing Transforming Growth Factor-β1 Levels in the Development of Vascular Defects in Endoglin Heterozygous Mice with Hereditary Hemorrhagic Telangiectasia

Abstract

No full-text available

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