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Vascular Endothelial Growth Factor Induces Abnormal Microvasculature in the Endoglin Heterozygous Mouse Brain

Lookup NU author(s): Professor Helen ArthurORCiD

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Abstract

Hereditary hemorrhagic telangiectasia (HHT), associated with brain arteriovenous malformations, is caused by a loss of function mutation in either the endoglin (HHT1) or activin receptor-like kinase 1 gene (ALK-1, HHT2). Endoglin heterozygous (Eng+/-)mice have been proposed as a disease model. To better understand the role of endoglin in vascular malformation development, we examined the effect of vascular endothelial growth factor (VEGF) hyperstimulation on microvessels in adult endoglin heterozygous (Eng +/-) mice using an adenoviral vector to deliver recombinant human VEGF165 cDNA (AdhVEGF) into basal ganglia. VEGF expression was increased in AdhVEGF mice compared with the AdlacZ and saline group (P < 0.05) and localized to multiple cell types (neurons, astrocytes, endothelial cells, and smooth muscle cells) by double-labeled immunostaining. VEGF overexpression increased microvessel count for up to 4 weeks in both the Eng+/+ and Eng+/- groups (Eng+/+ 185 ± 14 vs. Eng+/- 201 ± 10 microvessels/mm2). Confocal microscopic examination revealed grossly abnormal microvessels in eight of nine Eng+/- mouse brains compared with zero of nine in Eng+/+ mice (P < 0.05). Abnormal microvessels featured enlargement, clustering, twist, or spirals. VEGF receptor Flk-1 and TGF-β receptor 1 (TβR1) expression were reduced in the Eng+/- mouse brain compared with control. Excessive VEGF stimulation may play a pivotal role in the initiation and development of brain vessel malformations in states of relative endoglin insufficiency in adulthood. These observations are relevant to our general understanding of the maintenance of vascular integrity.


Publication metadata

Author(s): Xu B, Wu YQ, Huey M, Arthur HM, Marchuk DA, Hashimoto T, Young WL, Yang G-Y

Publication type: Article

Publication status: Published

Journal: Journal of Cerebral Blood Flow and Metabolism

Year: 2004

Volume: 24

Issue: 2

Pages: 237-244

ISSN (print): 0271-678X

ISSN (electronic): 1559-7016

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1097/01.WCB.0000107730.66603.51

DOI: 10.1097/01.WCB.0000107730.66603.51

PubMed id: 14747750


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Funding

Funder referenceFunder name
R01 NS27713NINDS NIH HHS
R21 NS45123NINDS NIH HHS

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