A Role for Endoglin in Coupling eNOS Activity and Regulating Vascular Tone Revealed in Hereditary Hemorrhagic Telangiectasia

Toporsian, Mourad; Gros, Robert; Kabir, M. Golam; Vera, Sonia; Govindaraju, Karuthapillai; Eidelman, David H.; Husain, Mansoor; Letarte, Michelle

doi:10.1161/01.res.0000159936.38601.22

Cited by 224 publications

(208 citation statements)

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“…160,168 Endogenous Smad phosphorylation in mural cells is reduced, 168 29,173 Support for a fundamental role for aberrant angiogenesis and reactive oxygen species in HHT disease pathogenesis is accumulating in man, with case reports and small series suggesting that anti-angiogenic and anti-oxidant strategies may be of therapeutic benefit in HHT (see Sections 4 and 5 below).…”

Section: 2d) Generation Of Abnormal Vessels In Hhtmentioning

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attractive experimental therapies promoted in high profile publications when guidelines and reviews are quickly superseded.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: 2d) Generation Of Abnormal Vessels In Hhtmentioning

confidence: 99%

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

2010

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“…The vasoregulatory protein endothelial nitric oxide synthase (eNOS) is decreased in endoglin-deficient cells, whereas it is increased in endoglinoverexpressing cells [Jerkic et al, 2004;Toporsian et al, 2005]. At least in part, the endoglindependent increase of eNOS levels is mediated by increased stabilization of eNOS protein in caveolae, via a post-transcriptional mechanism that involves direct association of endoglin with caveolar proteins and potentially heat shock protein 90 [Toporsian et al, 2005]. In addition, endoglin stabilizes the Smad2 protein, potentially via reduction in the levels of the Smad ubiquitination response factor 2, Smurf2 .…”

Section: Role Of Endoglin In the Modulation Of Tgfβ-dependent Cell Rementioning

confidence: 99%

Novel biochemical pathways of endoglin in vascular cell physiology

Bernabeu

Conley

Vary

2007

J of Cellular Biochemistry

119

123

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The broad role of the transforming growth factor beta (TGFβ) signaling pathway in vascular development, homeostasis, and repair is well appreciated. Endoglin is emerging as a novel, complex, and poorly understood regulatory component of the TGFβ receptor complex, whose importance is underscored by its recognition as the site of mutations causing hereditary hemorrhagic telangiectasia (HHT) [McAllister et al., 1994]. Extensive analyses of endoglin function in normal developmental mouse models [Bourdeau et al., 1999;Li et al., 1999;Arthur et al., 2000] and in HHT animal models [Bourdeau et al., 2000;Torsney et al., 2003] exemplify the importance of understanding endoglin's biochemical functions. However, novel mechanisms underlying the regulation of these pathways continue to emerge. These mechanisms include modification of TGFβ receptor signaling at the ligand and receptor activation level, direct effects of endoglin on cell adhesion and migration, and emerging roles for endoglin in the determination of stem cell fate and tissue patterning. The purpose of this review is to highlight the cellular and molecular studies that underscore the central role of endoglin in vascular development and disease. Keywords endoglin; transforming growth factor-beta receptors; hereditary hemorrhagic telangiectasia; vascular pathology; vascular endothelium; vascular smooth muscle The canonical transforming growth factor beta (TGFβ) signaling pathway comprises seven type I and five type II TGFβ receptors [Manning etal.,2002]. The TGFβ type I receptors are serine and threonine kinases, which include activin-like kinase 1 (ALK1) and TβRI, also known as ALK5. ALK1 and ALK5 associate with, and are activated via ligand-dependent phosphorylation [Vivien and Wrana, 1995] by the type II TGFβ receptor, TβRII [Wrana et al., 1992]. The activated type I receptor propagates canonical or Smad-dependent signals by phosphorylating Smad proteins [Shi and Massague, 2003;Feng and Derynck, 2005]. Another component of the TGFβ system is endoglin. Endoglin is a transmembrane protein [Gougos and Letarte, 1990] that acts as an auxiliary receptor for TGFβ [Cheifetz et al., 1992;Barbara et al., 1999]. Of note, mutations in endoglin (ENG) [McAllister et al., 1994] and ALK1 [Johnson et al., 1996] genes cause the vascular dysplasia hereditary hemorrhagic telangiectasia (HHT), termed HHT1 and HHT2, respectively.

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“…33,34 Interestingly, endoglin modulates endothelial NO synthase (eNOS) expression and activity, thus affecting vascular tone. [35][36][37] In the present study, we hypothesized that lower concentrations of relevant markers of NO formation (plasma and whole blood nitrite) would be found in hypertensive disorders of pregnancy compared with those found in healthy pregnancies. In addition, given the fact that sFLT-1 and sEng interfere with eNOS activity, we hypothesized that inverse relationships exist between the circulating concentrations of markers of NO formation and sFLT-1 or sEng during pregnancy.…”

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confidence: 92%

Nitric Oxide Formation Is Inversely Related to Serum Levels of Antiangiogenic Factors Soluble Fms-Like Tyrosine Kinase-1 and Soluble Endogline in Preeclampsia

et al. 2008

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Abstract-Deficient NO formation has been implicated in hypertensive disorders of pregnancy. However, no previous study has compared the circulating nitrite concentrations in healthy pregnant women with those found in hypertensive disorders of pregnancy. Moreover, 2 antiangiogenic factors produced in the placenta (soluble fms-like tyrosine kinase-1 and soluble endogline) may affect NO formation during pregnancy. Here, we hypothesized that lower concentrations of markers of NO formation exist in hypertensive disorders of pregnancy and that inverse relationships exist between these markers and soluble fms-like tyrosine kinase-1 or soluble endogline. In this cross-sectional study, we compared 58 healthy pregnant women with 56 gestational hypertensive subjects and 45 preeclamptic patients. We measured plasma and whole blood nitrite concentrations using an ozone-based chemiluminescence assay and serum soluble fms-like tyrosine kinase-1 and soluble endogline concentrations using enzyme immunoassays. Whole blood nitrite levels were significantly lower in gestational hypertensive subjects and preeclamptic patients (Ϫ36% and Ϫ58%, respectively; both PϽ0.05) compared with healthy pregnant women. The plasma nitrite levels were Ϸ37% lower in both groups with hypertensive disorders of pregnancy compared with the group with normotensive pregnancies (both PϽ0.05). As expected, we found higher circulating soluble fms-like tyrosine kinase-1 and soluble endogline concentrations in preeclampsia compared with gestational hypertensive subjects or with healthy pregnancies (both PϽ0.05). Key Words: NO Ⅲ nitrite Ⅲ whole blood nitrite Ⅲ preeclampsia Ⅲ sEng Ⅲ sFLT-1 N ormal human pregnancy is accompanied by increased blood volume that is accommodated within the cardiovascular system by systemic vasodilatation. 1 This vasodilatation involves increased NO formation, thus decreasing peripheral vascular resistance in healthy pregnant women. 2,3 On the other hand, deficient NO formation has been implicated in hypertensive disorders of pregnancy, such as preeclampsia and gestational hypertension. 4 -7 Indeed, previous studies compared the circulating concentrations of NO metabolites (nitriteϩnitrate) in the plasma from preeclamptic women with those found in healthy pregnant women. 8 -13 Conflicting results were reported, and some studies showed higher, 14 similar, 10,12 or lower 8 nitriteϩnitrate levels in preeclamptic women compared with healthy pregnant women. A possible explanation for these discrepancies is that nitriteϩnitrate may not accurately reflect endogenous NO formation in vivo, and there is mounting evidence that measuring the circulating concentrations of nitrite is an improved alternative to assess endogenously produced NO. [15][16][17][18][19] However, no previous study has compared the circulating nitrite concentrations in healthy pregnant women with those found in women with preeclampsia.The pathophysiology of preeclampsia is not completely known. However, there is evidence that a failure of cytotrophoblast invasion and abse...

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A Role for Endoglin in Coupling eNOS Activity and Regulating Vascular Tone Revealed in Hereditary Hemorrhagic Telangiectasia

Cited by 224 publications

References 41 publications

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Novel biochemical pathways of endoglin in vascular cell physiology

Nitric Oxide Formation Is Inversely Related to Serum Levels of Antiangiogenic Factors Soluble Fms-Like Tyrosine Kinase-1 and Soluble Endogline in Preeclampsia

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