title: VEGF Induces More Severe Cerebrovascular Dysplasia in Endoglin than in Alk1 Mice.
abstract: Brain arteriovenous malformations (BAVMs) are an important cause of intracranial hemorrhage (ICH) in young adults. A small percent of BAVMs is due to hereditary hemorrhagic telangiectasia 1 and 2 (HHT1 and 2), which are caused by mutations in two genes involved in TGF-β signaling: endoglin (ENG) and activin-like kinase 1 (ALK1). The BAVM phenotype is an incomplete penetrant in HHT patients, and the mechanism is unknown. We tested the hypothesis that a "response-to-injury" triggers abnormal vascular (dysplasia) development, using Eng and Alk1 haploinsufficient mice. Adeno-associated virus (AAV) expressing vascular endothelial growth factor (VEGF) was used to mimic the injury conditions. VEGF overexpression caused a similar degree of angiogenesis in the brain of all groups, except that the cortex of Alk1(+/-) mice had a 33% higher capillary density than other groups. There were different levels of cerebrovascular dysplasia in haploinsufficient mice (Eng(+/)>Alk1(+/-)), which simulates the relative penetrance of BAVM in HHT patients (HHT1>HHT2). Few dysplastic capillaries were observed in AAV-LacZ-injected mice. Our data indicate that both angiogenic stimulation and genetic alteration are necessary for the development of dysplasia, suggesting that anti-angiogenic therapies might be adapted to slow the progression of the disease and decrease the risk of spontaneous ICH.
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Avenue Room 3C-38, San Francisco, CA 94110, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Hao
authors.forename: Yiqian
authors.initials: Y
authors.lastname: Zhu
authors.forename: Hua
authors.initials: H
authors.lastname: Su
authors.forename: Fanxia
authors.initials: F
authors.lastname: Shen
authors.forename: Guo-Yuan
authors.initials: GY
authors.lastname: Yang
authors.forename: Helen
authors.initials: H
authors.lastname: Kim
authors.forename: William L
authors.initials: WL
authors.lastname: Young