Key Role of the Endothelial TGF-β/ALK1/Endoglin Signaling Pathway in Humans and Rodents Pulmonary Hypertension
Benoît GoreMohamed IzikkiOlaf MercierLaurence DewachterÉlie FadelMarc HumbertPhilippe DartevelleGérald SimonneauRobert NaeijeFranck LebrinSaadia Eddahibi
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Mutations affecting transforming growth factor-beta (TGF-β) superfamily receptors, activin receptor-like kinase (ALK)-1, and endoglin (ENG) occur in patients with pulmonary arterial hypertension (PAH). To determine whether the TGF-β/ALK1/ENG pathway was involved in PAH, we investigated pulmonary TGF-β, ALK1, ALK5, and ENG expressions in human lung tissue and cultured pulmonary-artery smooth-muscle-cells (PA-SMCs) and pulmonary endothelial cells (PECs) from 14 patients with idiopathic PAH (iPAH) and 15 controls. Seeing that ENG was highly expressed in PEC, we assessed the effects of TGF-β on Smad1/5/8 and Smad2/3 activation and on growth factor production by the cells. Finally, we studied the consequence of ENG deficiency on the chronic hypoxic-PH development by measuring right ventricular (RV) systolic pressure (RVSP), RV hypertrophy, and pulmonary arteriolar remodeling in ENG-deficient (Eng+/−) and wild-type (Eng+/+) mice. We also evaluated the pulmonary blood vessel density, macrophage infiltration, and cytokine expression in the lungs of the animals. Compared to controls, iPAH patients had higher serum and pulmonary TGF-β levels and increased ALK1 and ENG expressions in lung tissue, predominantly in PECs. Incubation of the cells with TGF-β led to Smad1/5/8 phosphorylation and to a production of FGF2, PDGFb and endothelin-inducing PA-SMC growth. Endoglin deficiency protected mice from hypoxic PH. As compared to wild-type, Eng+/− mice had a lower pulmonary vessel density, and no change in macrophage infiltration after exposure to chronic hypoxia despite the higher pulmonary expressions of interleukin-6 and monocyte chemoattractant protein-1. The TGF-β/ALK1/ENG signaling pathway plays a key role in iPAH and experimental hypoxic PH via a direct effect on PECs leading to production of growth factors and inflammatory cytokines involved in the pathogenesis of PAH.Keywords:
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Right ventricular hypertrophy
IntroductionHereditary hemorrhagic telangiectasia (HHT), also referred to as the Osler-Weber-Rendu syndrome, is a rare autosomal dominant hereditary disease that results in abnormal vasculogenesis in the skin, mucous membranes, and visceral organs such as the liver, lungs, and brain [1]. The prevalence of HHT ranges from one in every 5,000 people to one in every 8,000 people with an estimated 85,000 cases in Europe [2, 3] and the rate of diagnosis is lower in lower socioeconomic groups [4].Four important genes, including ENG (endoglin), ACVRL1 (activin receptor-like kinase 1), SMAD4 (mothers against decapentaplegic homolog 4), and GDF2 (growth differentiation factor 2), have recently been linked to the underlying mechanism of HHT [5]. Arterio-venous malformations (AVMs) are caused by mutations in these genes that interfere with the TGF-β (transforming growth factor)-beta signaling pathways in vascular endothelial cells, which impair cell division [5]. Heterozygous mutations are the common cause of the two primary kinds of HHT. Endoglin (ENG) is mutated in HHT1. Patients, especially women, with this type are more likely to develop pulmonary and cerebral AVMs. Activin A receptor-like type 1 (ACVRL1), commonly referred to as ALK1, is mutated in HHT2. Of the mutations known to cause HHT, ENG makes up around 61% and ACVRL1 makes up about 37% [7, 8].About 90% of those with the condition experience recurrent nosebleeds, which usually begin in childhood. Other symptoms include gastrointestinal bleeding (25–30%), which can cause melena and severe symptomatic microcytic anemia; pulmonary AVMs (50%) that can cause dyspnea, hemoptysis, paradoxical emboli, and cerebral abscesses; cerebral AVMs (10%) that can cause headache, seizures, and focal neurological deficits; and hepatic AVM (40–70%), which are typically asymptomatic but might show signs of high output cardiac failure and hepatic decompensation, ultimately necessitating liver transplantation [9].Clinical diagnosis of HHT is made using the Curacao criteria, which include first-degree family history of HHT, visceral involvement, recurrent spontaneous nosebleeds, and mucocutaneous telangiectasias. If three or more criteria are met, the diagnosis is considered to be conclusive; if only two criteria are met, the diagnosis is considered to be suspected HHT [10] [Table 1]. If less than two criteria are met, the diagnosis is considered to be unlikely HHT.Table 1 Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasias
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Studies of rare genetic diseases frequently reveal genes that are fundamental to life, and the familial vascular disorder HHT (hereditary haemorrhagic telangiectasia) is no exception. The majority of HHT patients are heterozygous for mutations in either the ENG (endoglin) or the ACVRL1 (activin receptor-like kinase 1) gene. Both genes are essential for angiogenesis during development and mice that are homozygous for mutations in Eng or Acvrl1 die in mid-gestation from vascular defects. Recent development of conditional mouse models in which the Eng or Acvrl1 gene can be depleted in later life have confirmed the importance of both genes in angiogenesis and in the maintenance of a normal vasculature. Endoglin protein is a co-receptor and ACVRL1 is a signalling receptor, both of which are expressed primarily in endothelial cells to regulate TGFβ (transforming growth factor β) signalling in the cardiovasculature. The role of ACVRL1 and endoglin in TGFβ signalling during angiogenesis is now becoming clearer as interactions between these receptors and additional ligands of the TGFβ superfamily, as well as synergistic relationships with other signalling pathways, are being uncovered. The present review aims to place these recent findings into the context of a better understanding of HHT and to summarize recent evidence that confirms the importance of endoglin and ACVRL1 in maintaining normal cardiovascular health.
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Introduction: Hereditary Haemorrhagic Telangiectasia (HHT) is as an autosomal dominant trait characterized by frequent nose bleeds, mucocutaneous telangiectases, arteriovenous malformations (AVMs) of the lung, liver and brain, and gastrointestinal bleedings due to telangiectases. HHT is originated by mutations in genes whose encoded proteins are involved in the transforming growth factor β (TGF-β) family signalling of vascular endothelial cells. In spite of the great advances in the diagnosis as well as in the molecular, cellular and animal models of HHT, the current treatments remain just at the palliative level.Areas covered: Pathogenic mutations in genes coding for the TGF-β receptors endoglin (ENG) (HHT1) or the activin receptor-like kinase-1 (ACVRL1 or ALK1) (HHT2), are responsible for more than 80% of patients with HHT. Therefore, ENG and ALK1 are the main potential therapeutic targets for HHT and the focus of this review. The current status of the preclinical and clinical studies, including the anti-angiogenic strategy, have been addressed.Expert opinion: Endoglin and ALK1 are attractive therapeutic targets in HHT. Because haploinsufficiency is the pathogenic mechanism in HHT, several therapeutic approaches able to enhance protein expression and/or function of endoglin and ALK1 are keys to find novel and efficient treatments for the disease.
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Hereditary haemorrhagic telangiectasia (HHT) (OMIM 187300) is an autosomal dominant disorder caused by mutations in either of two genes, endoglin ( ENG , OMIM 131195) (HHT1) and activin A receptor type II-like 1 ( ACVRL1 , OMIM 601284) (HHT2). Evidence for a third locus has also been reported.1
The product of the ACVRL1 gene is a type I receptor for the TGF-beta group of ligands; it is associated with the TGF-beta or activin type II receptors and the complex binds TGF-beta or activin. It is highly expressed in endothelial cells, lung, and placenta, as endoglin, mutations of which are observed in HHT1; endoglin is supposed to sequester TGF-beta and present the ligand to activin A receptor type II-like 1 plus a type II receptor.2 Mutations in ENG and ACVRL1 may cause HHT1 or HHT2, respectively, by disrupting this complex.
The clinical presentation, indistinguishable between HHT1 and HHT2, typically includes epistaxis and telangiectasia, and the diagnosis can be considered to be confirmed, according to the proposal of Shovlin et al ,3 if three of the four suggested diagnostic criteria (epistaxis, telangiectasia, visceral lesions, positive family history) are present. The phenotype is highly variable and penetrance is complete by the age of 40 years.4
Arteriovenous (AV) fistulae are frequently observed in the liver (8% of patients),5 lungs (20%),6 and brain5 and may cause severe life threatening complications. Neurological complications (strokes, cerebral abscesses, seizures) may be prevented with appropriate treatment of the pulmonary arteriovenous malformations (PAVMs). A higher risk for lung involvement has been suggested in patients carrying mutations in the ENG gene,7 while in some families with a peculiar liver involvement, mutations in ACVRL1 have been described.8 The involvement of the latter gene has also been reported in a single patient with a pituitary tumour …
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Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplastic disorder, characterized by recurrent nosebleeds (epistaxis), multiple telangiectases and arteriovenous malformations (AVMs) in major organs. Mutations in Endoglin (ENG or CD105) and Activin receptor-like kinase 1 (ACVRL1 or ALK1) genes of the TGF-β superfamily receptors are responsible for HHT1 and HHT2 respectively and account for the majority of HHT cases. Haploinsufficiency in ENG and ALK1 is recognized at the underlying cause of HHT. However, the mechanisms responsible for the predisposition to and generation of AVMs, the hallmark of this disease, are poorly understood. Recent data suggest that dysregulated angiogenesis contributes to the pathogenesis of HHT and that the vascular endothelial growth factor, VEGF, may be implicated in this disease, by modulating the angiogenic-angiostatic balance in the affected tissues. Hence, anti-angiogenic therapies that target the abnormal vessels and restore the angiogenic-angiostatic balance are candidates for treatment of HHT. Here we review the experimental evidence for dysregulated angiogenesis in HHT, the anti-angiogenic therapeutic strategies used in animal models and some patients with HHT and the potential benefit of the anti-angiogenic treatment for ameliorating this severe, progressive vascular disease.
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Abstract Objective As an initial approach to understanding the basis of the systemic sclerosis (SSc; scleroderma) phenotype, we sought to identify genes in the transforming growth factor β (TGFβ) signaling pathway that are up‐regulated in lesional SSc fibroblasts relative to their normal counterparts. Methods We used gene chip, differential display, fluorescence‐activated cell sorter, and overexpression analyses to assess the potential role of TGFβ signaling components in fibrosis. Fibroblasts were obtained by punch biopsy from patients with diffuse cutaneous SSc of 2–14 months' duration (mean 8 months) and from age‐ and sex‐matched healthy control subjects. Results Unexpectedly, we found that fibroblasts from SSc patients showed elevated expression of the endothelial cell–enriched TGFβ receptor endoglin. Endoglin is a member of the nonsignaling high‐affinity TGFβ receptor type III family. The expression of endoglin increased with progression of disease. Transfection of endoglin in fibroblasts suppressed the TGFβ‐mediated induction of connective tissue growth factor promoter activity. Conclusion SSc is characterized by overproduction of matrix; that is, genes that are targets of TGFβ signaling in normal fibroblasts. Our findings suggest that lesional SSc fibroblasts may overexpress endoglin as a negative feedback mechanism in an attempt to block further induction of profibrotic genes by TGFβ.
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A decade ago, it was recognized that mutations in the ENDOGLIN (ENG) (1) and ACTIVIN RECEPTOR-LIKE KINASE 1 (ACVRL1) (2) genes cause an autosomal dominant disorder known as hereditary hemorrhagic telangiectasia (HHT) type 1 and type 2, respectively. The predominant expression of the corresponding proteins, endoglin and ALK1, on vascular endothelial cells (ECs) and their function as transforming growth factor (TGF)-β receptors indicated that HHT is likely associated with perturbations in TGF-β signaling in ECs. Mice heterozygous for either gene develop HHT (3–6), and can be used to gain insight into the mechanisms of disease, highlighting the role of TGF-β in maintaining vascular integrity and unraveling the potential contribution of other pathways to HHT pathogenesis. Mice totally deficient in either endoglin (3–5) or ALK1 (6) do not survive past midgestation, and their analysis has revealed an essential role for these receptors in vascular development. This chapter provides an overview of HHT as a disorder of the vascular endothelium associated with the generation of abnormal structures such as telangiectases and arteriovenous malformations (AVMs), and discusses the current model of HHT pathogenesis.
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Hereditary haemorrhagic telangiectasia (HHT) is a vascular hereditary autosomic dominant disease associated with epistaxis, telangiectases, gastrointestinal haemorrhages and arteriovenous malformations in lung, liver and brain. It affects 1-2 in 10,000 people. There are at least three different genes mutated in HHT, ENG, ACVRL1 and MADH4 that encode endoglin, activin receptor-like kinase (ALK1) and Smad4 proteins, respectively. These proteins are involved in the transforming growth factor (TGF)-β superfamily signalling pathway of vascular endothelial cells. Mutations in ENG (HHT1) and ACVRL1 (HHT2) account for more than 90% of all HHT mutations. In this article, we review the underlying molecular and cellular bases and the therapeutic approaches that have been addressed in our laboratory in recent years.
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Rare inherited cardiovascular diseases are frequently caused by mutations in genes that are essential for the formation and/or function of the cardiovasculature. Hereditary Haemorrhagic Telangiectasia is a familial disease of this type. The majority of patients carry mutations in either Endoglin (ENG) or ACVRL1 (also known as ALK1) genes, and the disease is characterized by arteriovenous malformations and persistent haemorrhage. ENG and ACVRL1 encode receptors for the TGFβ superfamily of ligands, that are essential for angiogenesis in early development but their roles are not fully understood. Our goal was to examine the role of Acvrl1 in vascular endothelial cells during vascular development and to determine whether loss of endothelial Acvrl1 leads to arteriovenous malformations. Acvrl1 was depleted in endothelial cells either in early postnatal life or in adult mice. Using the neonatal retinal plexus to examine angiogenesis, we observed that loss of endothelial Acvrl1 led to venous enlargement, vascular hyperbranching and arteriovenous malformations. These phenotypes were associated with loss of arterial Jag1 expression, decreased pSmad1/5/8 activity and increased endothelial cell proliferation. We found that Endoglin was markedly down-regulated in Acvrl1-depleted ECs showing endoglin expression to be downstream of Acvrl1 signalling in vivo. Endothelial-specific depletion of Acvrl1 in pups also led to pulmonary haemorrhage, but in adult mice resulted in caecal haemorrhage and fatal anaemia. We conclude that during development, endothelial Acvrl1 plays an essential role to regulate endothelial cell proliferation and arterial identity during angiogenesis, whilst in adult life endothelial Acvrl1 is required to maintain vascular integrity.
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Genetic studies in mice and humans have revealed the pivotal role of transforming growth factor-beta (TGF-beta) signaling during angiogenesis. Mice deficient for various TGF-beta signaling components present an embryonic lethality due to vascular defects. In patients, mutations in the TGF-beta type I receptor ALK1 or in the accessory TGF-beta receptor endoglin are linked to an autosomal dominant disorder of vascular dysplasia termed Hereditary Haemorrhagic Telangiectasia (HHT). It has puzzled researchers for years to explain the effects of TGF-beta being a stimulator and an inhibitor of angiogenesis in vitro and in vivo. Recently, a model has been proposed in which TGF-beta by binding to the TGF-beta type II receptor can activate two distinct type I receptors in endothelial cells (ECs), i.e., the EC-restricted ALK1 and the broadly expressed ALK-5, which have opposite effects on ECs behavior. ALK1 via Smad1/5 transcription factors stimulates EC proliferation and migration, whereas ALK5 via Smad2/3 inhibits EC proliferation and migration. Here, the new findings are presented concerning the molecular mechanisms that take place in ECs to precisely regulate and even switch between TGF-beta-induced biological responses. In particular, the role of the accessory TGF-beta receptor endoglin in the regulation of EC behavior is addressed and new insights are discussed concerning the possible mechanisms that are implicated in the development of HHT.
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