| Pathogenesis of arteriovenous malformations in the absence of endoglin. | |
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MedLine Citation:
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PMID: 20224041 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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RATIONALE: Arteriovenous malformations (AVMs) result in anomalous direct blood flow between arteries and veins, bypassing the normal capillary bed. Depending on size and location, AVMs may lead to severe clinical effects including systemic cyanosis (pulmonary AVMs), hemorrhagic stroke (cerebral AVMs) and high output cardiac failure (hepatic AVMs). The factors leading to AVM formation are poorly understood, but patients with the familial disease hereditary hemorrhagic telangiectasia (HHT) develop AVMs at high frequency. As most HHT patients have mutations in ENG (endoglin) or ACVRL1 (activin receptor-like kinase 1), a better understanding of the role of these genes in vascular development is likely to reveal the etiology of AVM formation. OBJECTIVE: Using a mouse with a conditional mutation in the Eng gene, we investigated the sequence of abnormal cellular events occurring during development of an AVM. METHODS AND RESULTS: In the absence of endoglin, subcutaneous Matrigel implants in adult mice were populated by reduced numbers of new blood vessels compared with controls, and resulted in local venous enlargement (venomegaly). To investigate abnormal vascular responses in more detail, we turned to the more readily accessible vasculature of the neonatal retina. Endoglin-deficient retinas exhibited delayed remodeling of the capillary plexus, increased proliferation of endothelial cells and localized AVMs. Muscularization of the resulting arteriovenous shunts appeared to be a secondary response to increased blood flow. CONCLUSIONS: AVMs develop when an angiogenic stimulus is combined with endoglin depletion. Moreover, AVM formation appears to result from the combination of delayed vascular remodeling and an inappropriate endothelial cell proliferation response in the absence of endoglin. |
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Authors:
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Marwa Mahmoud; Kathleen R Allinson; Zhenhua Zhai; Rachael Oakenfull; Pranita Ghandi; Ralf H Adams; Marcus Fruttiger; Helen M Arthur |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-03-11 |
Journal Detail:
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Title: Circulation research Volume: 106 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-30 Completed Date: 2010-05-24 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 1425-33 Citation Subset: IM |
Affiliation:
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Institute of Human Genetics, Centre for Life, Newcastle University, NE1 3BZ, United Kingdom. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aging Angiogenic Proteins / metabolism Animals Antigens, CD / genetics Arteriovenous Malformations / genetics, metabolism, pathology*, physiopathology Cadherins / genetics Capillaries / metabolism, pathology Cell Proliferation* Endothelial Cells / metabolism, pathology* Integrases / genetics Intracellular Signaling Peptides and Proteins / deficiency*, genetics Mice Mice, Knockout Mice, Transgenic Microcirculation Mutation* Neovascularization, Pathologic / genetics, metabolism, pathology*, physiopathology Regional Blood Flow Retinal Neovascularization / genetics, metabolism, pathology*, physiopathology |
| Grant Support | |
ID/Acronym/Agency:
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//British Heart Foundation; //Wellcome Trust |
| Chemical | |
Reg. No./Substance:
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0/Angiogenic Proteins; 0/Antigens, CD; 0/Cadherins; 0/Intracellular Signaling Peptides and Proteins; 0/cadherin 5; 0/endoglin protein, mouse; EC 2.7.7.-/Cre recombinase; EC 2.7.7.-/Integrases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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