Fine mapping of the hereditary haemorrhagic telangiectasia (HHT)3 locus on chromosome 5 excludes VE-Cadherin-2, Sprouty4 and other interval genes

Govani, Fatima S; Shovlin, CL

doi:10.1186/2040-2384-2-15

Cited by 16 publications

(13 citation statements)

References 53 publications

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“…Vascular branching is disturbed in the MGP transgenic mice, which exhibit loss of side branching and stunted growth of pulmonary arteries 67 . AVMs, on the other hand, are characteristic of ALK1 deficiency 71 and can be described as a short-circuited and disrupted network in the capillary bed. Because ALK1 is regulated by BMP4 and in turn regulates MGP, the balance between BMP4 and MGP is likely to affect the capillary network.…”

Section: Role Of Bmp Signaling In Vascular Biology and Calcific Vascmentioning

confidence: 99%

The Regulation of Valvular and Vascular Sclerosis by Osteogenic Morphogens

Boström

Rajamannan

Towler

2011

Circulation Research

225

201

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Vascular calcification increasingly afflicts our aging, dysmetabolic population. Once considered only a passive process of dead and dying cells, vascular calcification has now emerged as a highly regulated form of biomineralization organized by collagenous and elastin extracellular matrices. During skeletal bone formation, paracrine epithelial-mesenchymal and endothelial-mesenchymal interactions control osteochondrocytic differentiation of multipotent mesenchymal progenitor cells. These paracrine osteogenic signals, mediated by potent morphogens of the BMP and Wnt superfamilies, are also active in the programming of arterial osteoprogenitor cells during vascular and valve calcification. Inflammatory cytokines, reactive oxygen species and oxylipids – increased in the clinical settings of atherosclerosis, diabetes, and uremia that promote arteriosclerotic calcification – elicit the ectopic vascular activation of osteogenic morphogens. Specific extracellular and intracellular inhibitors of BMP-Wnt signaling have been identified as contributing to the regulation of osteogenic mineralization during development and disease. These inhibitory pathways and their regulators afford the development of novel therapeutic strategies to prevent and treat valve and vascular sclerosis.

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Section: Role Of Bmp Signaling In Vascular Biology and Calcific Vascmentioning

confidence: 99%

The Regulation of Valvular and Vascular Sclerosis by Osteogenic Morphogens

Boström

Rajamannan

Towler

2011

Circulation Research

225

201

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“…20 One to two percent of cases 127 have mutations in SMAD4, mutations that also cause the gastrointestinal epithelial precancerous state of juvenile polyposis. 11 There are at least two further unidentified genes that can cause pure HHT, HHT3 between 141.9-146.4Mb on chromosome 5q, 128,129 and HHT4 on chromosome 7p between D7S2252 and D7S510. 130 More than 600 different mutations have been found in ENG and ACVRL1 in HHT families ( 21 , summarised in 3 ).…”

Section: 2a) Geneticsmentioning

confidence: 99%

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

2010

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Hereditary haemorrhagic telangiectasia, inherited as an autosomal dominant trait, affects approximately 1 in 5,000 people. The abnormal vascular structures in HHT result from mutations in genes (most commonly endoglin or ACVRL1) whose protein products influence TGF-ß superfamily signalling in vascular endothelial cells. The cellular mechanisms underlying the generation of HHT telangiectasia and arteriovenous malformations are being unravelled, with recent data focussing on a defective response to angiogenic stimuli in particular settings. For affected individuals, there is often substantial morbidity due to sustained and repeated haemorrhages from telangiectasia in the nose and gut. Particular haematological clinical challenges include the management of severe iron deficiency anaemia; handling the intricate balance of antiplatelet or anticoagulants for HHT patients in whom there are often compelling clinical reasons to use such agents; and evaluation of apparently attractive experimental therapies promoted in high profile publications when guidelines and reviews are quickly superseded. There is also a need for sound screening programmes for silent arteriovenous malformations. These occur commonly in the pulmonary, cerebral, and hepatic circulations, may haemorrhage, but predominantly result in more complex pathophysiology due to consequences of defective endothelium, or shunts that bypass specific capillary beds. This review will focus on the new evidence and concepts in this complex and fascinating condition, placing these in context for both clinicians and scientists, with a particular emphasis on haematological settings. Blood Reviews _ HHT 2010_ Shovlin 3 Overview of HHTHHT, also known as Osler Weber Rendu syndrome [1][2][3] , is one of the most common disorders to be inherited as an autosomal dominant trait. Careful epidemiological studies reveal that it affects approximately 1 in 5,000 individuals, 4,5 with regional differences, 6 and isolated communities displaying higher prevalences due to founder effects. 7 8 HHT was first described as a familial disease characterised by severe recurrent nasal and gastrointestinal bleeding with associated anaemia, and visible dilated blood vessels (telangiectasia) on the lips and finger tips. The majority of HHT patients are also affected by larger arteriovenous malformations (AVMs) in the pulmonary, hepatic, cerebral, pancreatic, spinal and other circulations. 1,2,9 These features, presented in more detail within Table 1, are used as criteria to diagnose HHT. 2 The spectrum of disease within the HHT umbrella has extended beyond the telangiectatic/AVM HHT pathology delineated by the Curaçao criteria. 2 More recently recognised features include pulmonary arterial hypertension 10 ; juvenile polyposis 11 ; pulmonary hypertension in the context of high output cardiac failure secondary to hepatic AVMs, when PH may be reversible after hepatic AVM treatment [12][13][14][15][16] ; a prothrombotic state associated with elevated plasma levels of factor VIII 17 , and poten...

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“…We found that endoglin negatively regulates the PPP2R2B/NOS3 interaction and controls the basal level of NOS3 Ser1177 phosphorylation. The PPP2R2B gene being a candidate for the HHT3 locus (16,17), our findings suggest a critical role for the corresponding regulatory subunit in recruiting TGF-␤ receptors and PP2A to the NOS3 activation complex in endothelial cells, thereby modulating vascular homeostasis.…”

Section: Discussionmentioning

confidence: 97%

“…However, the mechanisms governing recruitment of PP2A to NOS3 and the contribution of TGF-␤/BMP receptor complexes are unknown. Recently, the human PPP2R2B gene coding for PPP2R2B protein (also known as PP2A-B␤ regulatory subunit) was mapped to chromosome 5q31-q32, in an interval in linkage disequilibrium with the HHT3 locus (16,17). We now report that PPP2R2B interacts with the ACVRL1/ TGFBR2/endoglin complex and that endoglin governs NOS3 phosphorylation and activation status by hindering PP2A access to NOS3 via the PPP2R2B subunit.…”

mentioning

confidence: 94%

Novel Protein Interactions with Endoglin and Activin Receptor-like Kinase 1: Potential Role in Vascular Networks

Barrios‐Rodiles

Jerkić

et al. 2014

Molecular & Cellular Proteomics

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Endoglin and activin receptor-like kinase 1 are specialized transforming growth factor-beta (TGF-␤) superfamily receptors, primarily expressed in endothelial cells. Mutations in the corresponding ENG or ACVRL1 genes lead to hereditary hemorrhagic telangiectasia (HHT1 and HHT2 respectively). To discover proteins interacting with endoglin, ACVRL1 and TGF-␤ receptor type 2 and involved in TGF-␤ signaling, we applied LUMIER, a high-throughput mammalian interactome mapping technology. Using stringent criteria, we identified 181 novel unique and shared interactions with ACVRL1, TGF-␤ receptor type 2, and endoglin, defining potential novel important vascular networks. In particular, the regulatory subunit B-beta of the protein phosphatase PP2A (PPP2R2B) interacted with all three receptors. Interestingly, the PPP2R2B gene lies in an interval in linkage disequilibrium with HHT3, for which the gene remains unidentified. We show that PPP2R2B protein interacts with the ACVRL1/TGFBR2/endoglin complex and recruits PP2A to nitric oxide synthase 3 (NOS3). Endoglin overexpression in endothelial cells inhibits the association of PPP2R2B with NOS3, whereas endoglin-deficient cells show enhanced PP2A-NOS3 interaction and lower levels of endogenous NOS3 Serine 1177 phosphorylation. Our data suggest that endoglin regulates NOS3 activation status by regulating PPP2R2B access to NOS3, and that PPP2R2B might be the HHT3 gene. Furthermore, endoglin and ACVRL1 contribute to several novel networks, including TGF-␤ dependent and independent ones, critical for vascular function and potentially defective in HHT. Molecular & Cellular Proteomics 13: 10.1074/mcp.M113.033464, 489-502, 2014. Transforming growth factor-␤ (TGF-␤)1 superfamily ligands, including TGF-␤s, activins and bone morphogenic proteins (BMPs), regulate several pathways essential for vascular development and function (1). Responses to these ligands are controlled by type I and II serine kinase receptors, coreceptors and signaling SMAD intermediates. Endothelial cells express the coreceptor, endoglin, and the specialized type I receptor, ACVRL1 (activin receptor-like kinase 1 or ALK1); both molecules are critical for regulation of angiogenesis and vasomotor function by TGF-␤ superfamily ligands (2, 3).Mutations in ENG and ACVRL1 genes lead to hereditary hemorrhagic telangiectasia (HHT), types 1 and 2, respectively (4). HHT affects 1 in 5000 -8000 people worldwide and is characterized by arteriovenous malformations (AVMs) in mul-

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Fine mapping of the hereditary haemorrhagic telangiectasia (HHT)3 locus on chromosome 5 excludes VE-Cadherin-2, Sprouty4 and other interval genes

Cited by 16 publications

References 53 publications

The Regulation of Valvular and Vascular Sclerosis by Osteogenic Morphogens

The Regulation of Valvular and Vascular Sclerosis by Osteogenic Morphogens

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Novel Protein Interactions with Endoglin and Activin Receptor-like Kinase 1: Potential Role in Vascular Networks

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