Spontaneous Adult-Onset Pulmonary Arterial Hypertension Attributable to Increased Endothelial Oxidative Stress in a Murine Model of Hereditary Hemorrhagic Telangiectasia

Toporsian, Mourad; Jerkić, Mirjana; Zhou, Yuqing; Kabir, M. Golam; Yu, Lisa; McIntyre, Brendan A.S.; Davis, Adrienne; Wang, Yu Jing; Stewart, Duncan J.; Belik, Jaques; Husain, Mansoor; Henkelman, Mark; Letarte, Michelle

doi:10.1161/atvbaha.109.200121

Cited by 45 publications

(40 citation statements)

References 37 publications

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“…Juvenile polyposis (JP) occurs in patients with SMAD4 mutations, when it appears to be indistinguishable from JP caused by BMPRIA mutations. In man (but not in mouse 133 ), pulmonary arterial hypertension occurs predominantly and possibly exclusively within HHT2 patients 102,134,135 , when it may have a worse prognosis than when due to BMPR2 mutations 102 . HHT2 patients are also at higher risk of post capillary pulmonary hypertension associated with hepatic AVMs.…”

Section: 2b) Genotype Phenotype Correlationsmentioning

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attractive experimental therapies promoted in high profile publications when guidelines and reviews are quickly superseded.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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Section: 2b) Genotype Phenotype Correlationsmentioning

confidence: 99%

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

2010

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“…Thus high levels of O 2 Ϫ and ONOO Ϫ , similarly to those reported in Eng ϩ/Ϫ mice (160), decreased NO availability and led to the nitration of PKG, a critical mediator of the NO-dependent vasodilatation. Consequently, an impaired endothelium-dependent relaxation was observed (178), as opposed to the increased endothelium-dependent vasodilatation found in Eng ϩ/Ϫ mice (160), although both animal models share the pulmonary hypertension phenotype (161,178).…”

Section: Endoglin and Regulation Of Vascular Tonementioning

confidence: 99%

The physiological role of endoglin in the cardiovascular system

López‐Novoa

Bernabeu

2010

American Journal of Physiology-Heart and Circulatory Physiology

185

197

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Endoglin (CD105) is an integral membrane glycoprotein that serves as a coreceptor for members of the transforming growth factor-β superfamily of proteins. A major role for endoglin in regulating transforming growth factor-β-dependent vascular remodeling and angiogenesis has been postulated based on the following: 1) endoglin is the gene mutated in hereditary hemorrhagic telangiectasia type 1, a disease characterized by vascular malformations; 2) endoglin knockout mice die at midgestation because of defective angiogenesis; 3) endoglin is overexpressed in neoangiogenic vessels, during inflammation, and in solid tumors; and 4) endoglin regulates the expression and activity of endothelial nitric oxide synthase, which is involved in angiogenesis and vascular tone. Besides the predominant form of the endoglin receptor (long endoglin isoform), two additional forms of endoglin have been recently reported to play a role in the vascular pathology and homeostasis: the alternatively spliced short endoglin isoform and a soluble endoglin form that is proteolytically cleaved from membrane-bound endoglin. The purpose of this review is to underline the role that the different forms of endoglin play in regulating angiogenesis, vascular remodeling, and vascular tone, as well as to analyze the molecular and cellular mechanisms supporting these effects.

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“…The data were then complemented by the most current release 3.2.100 of the BioGRID resource (24). In addition we manually extracted relevant interactions from several publications, which, to our knowledge, have not yet been annotated by public databases (2,3,25,26).…”

Section: Methodsmentioning

confidence: 99%

“…Interestingly, TGF-␤1 and -␤3 do not induce phosphorylation at NOS3 Ser1177, yet NOS3 activation in response to TGF-␤1 is abolished in endoglin-deficient cells, impairing vasomotor function (3). ACVRL1 (or ALK1) also interacts with NOS3, and its reduced levels in endothelial cells similarly cause NOS3-derived oxidative stress (3,9).…”

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confidence: 99%

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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Spontaneous Adult-Onset Pulmonary Arterial Hypertension Attributable to Increased Endothelial Oxidative Stress in a Murine Model of Hereditary Hemorrhagic Telangiectasia

Cited by 45 publications

References 37 publications

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

The physiological role of endoglin in the cardiovascular system

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

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