Angiogenic Stimuli and Endoglin Absence Induces Brain Arteriovenous Malformations: Are Local Endoglin Deletion and Angiogenesis the ‘Second Hit’ That Is Necessary for Arteriovenous Malformations Formation in HHT-1?

Jm, López-Novoa

doi:10.1159/000338772

Cited by 3 publications

(2 citation statements)

References 10 publications

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“…To explain this paradox, the need for a trigger such as inflammation, vascular injury, angiogenic stimuli, or ischemia has been postulated ( Park et al, 2009 ; López-Novoa and Bernabeu, 2010 ; Choi et al, 2014 ). In HHT1, this trigger would synergize with endoglin haploinsufficiency to generate the vascular lesion ( Lopez-Novoa, 2012 ; Choi et al, 2014 ). Interestingly, those stimuli are usually associated with the upregulated expression of endoglin in endothelial cells and an inflammatory cell infiltrate ( Torsney et al, 2002 ; López-Novoa and Bernabeu, 2010 ), suggesting the need of both, endoglin function and leukocyte infiltration, in the vascular repair/remodeling process.…”

Section: Is the Role Of Endoglin In Cell–cell Adhesion Involved In Hhmentioning

confidence: 99%

Endoglin involvement in integrin-mediated cell adhesion as a putative pathogenic mechanism in hereditary hemorrhagic telangiectasia type 1 (HHT1)

2015

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Mutations in the endoglin gene (ENG) are responsible for ∼50% of all cases with hereditary hemorrhagic telangiectasia (HHT). Because of the absence of effective treatments for HHT symptoms, studies aimed at identifying novel biological functions of endoglin which could serve as therapeutic targets of the disease are needed. Endoglin is an endothelial membrane protein, whose most studied function has been its role as an auxiliary receptor in the TGF-β receptor complex. However, several lines of evidence suggest the involvement of endoglin in TGF-β-independent functions. Endoglin displays, within its zona pellucida domain, an RGD motif, which is a prototypic sequence involved in integrin-based interactions with other proteins. Indeed, we have recently described a novel role for endothelial endoglin in leukocyte trafficking and extravasation via its interaction with leukocyte integrins. In addition, functional, as well as protein and gene expression analysis have shown that ectopic endoglin represses the synthesis of several members of the integrin family and modulates integrin-mediated cell adhesions. This review focuses on the tight link between endoglin and integrins and how the role of endothelial endoglin in integrin-dependent cell adhesion processes can provide a better understanding of the pathogenic mechanisms leading to vascular lesions in endoglin haploinsufficient HHT1 patients.

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Section: Is the Role Of Endoglin In Cell–cell Adhesion Involved In Hhmentioning

confidence: 99%

Endoglin involvement in integrin-mediated cell adhesion as a putative pathogenic mechanism in hereditary hemorrhagic telangiectasia type 1 (HHT1)

2015

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“…In recent years, attention has been given to the so-called second-hit hypothesis in HHT. The assumption here is that, in order to achieve a full clinical HHT phenotype, a second genetic hit (somatic mutation) at the wt allele of the ACVRL1 wt/mut gene is required and that the classical single HHT germline mutation alone possibly is not sufficient to produce a full blown HHT phenotype [ 37 , 38 , 39 , 40 , 41 ]. This was intriguingly and convincingly demonstrated by Snellings and coworkers: next to the existence of an inherited germline mutation within one allele of an HHT-related gene, they demonstrated the additional presence of a somatic mutation in the other allele of the same gene when performing a next-generation sequencing analysis of telangiectasias.…”

Section: Discussionmentioning

confidence: 99%

Generation of a Syngeneic Heterozygous ACVRL1(wt/mut) Knockout iPS Cell Line for the In Vitro Study of HHT2-Associated Angiogenesis

Xiang-Tischhauser,

Bette,

Rusche

et al. 2023

Cells

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Hereditary hemorrhagic telangiectasia (HHT) type 2 is an autosomal dominant disease in which one allele of the ACVRL1 gene is mutated. Patients exhibit disturbances in TGF-beta/BMP-dependent angiogenesis and, clinically, often present with severe nosebleeds as well as a reduced quality of life. The aim of our study was to use CRISPR/Cas9 to knockout ACVRL1 in normal induced pluripotent stem cells (iPSCs) and evaluate the effects on TGF-beta- and BMP-related gene expression as well as angiogenesis. The CRISPR/Cas9 knockout of the ACVRL1 gene was carried out in previously characterized wild-type (ACVRL1wt/wt) iPSCs. An HHT type 2 iPS cell line was generated via a single-allele knockout (ACVRL1wt/mut) in wild-type (ACVRL1wt/wt) iPSCs, resulting in a heterozygous 17 bp frameshift deletion in the ACVRL1 gene [NG_009549.1:g.13707_13723del; NM_000020.3:c.1137_1153del]. After the generation of embryoid bodies (EBs), endothelial differentiation was induced via adding 4 ng/mL BMP4, 2% B27, and 10 ng/mL VEGF. Endothelial differentiation was monitored via immunocytochemistry. An analysis of 151 TGF-beta/BMP-related genes was performed via RT-qPCR through the use of mRNA derived from single iPS cell cultures as well as endothelial cells derived from EBs after endothelial differentiation. Differential TGF-beta/BMP gene expression was observed between ACVRL1wt/wt as well as ACVRL1wt/mut iPSCs and endothelial cells. EBs derived from CRISPR/Cas9-designed ACVRL1 mutant HHT type 2 iPSCs, together with their isogenic wild-type iPSC counterparts, can serve as valuable resources for HHT type 2 in vitro studies.

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Physiological and Pathological Consequences of Vascular BMP Signaling

Benn

Haupt

Hildebrandt

et al. 2017

Bone Morphogenetic Proteins: Systems Biology Regulators

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Angiogenic Stimuli and Endoglin Absence Induces Brain Arteriovenous Malformations: Are Local Endoglin Deletion and Angiogenesis the ‘Second Hit’ That Is Necessary for Arteriovenous Malformations Formation in HHT-1?

Cited by 3 publications

References 10 publications

Endoglin involvement in integrin-mediated cell adhesion as a putative pathogenic mechanism in hereditary hemorrhagic telangiectasia type 1 (HHT1)

Endoglin involvement in integrin-mediated cell adhesion as a putative pathogenic mechanism in hereditary hemorrhagic telangiectasia type 1 (HHT1)

Generation of a Syngeneic Heterozygous ACVRL1(wt/mut) Knockout iPS Cell Line for the In Vitro Study of HHT2-Associated Angiogenesis

Physiological and Pathological Consequences of Vascular BMP Signaling

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