title: Vascular endothelial growth factor induces abnormal microvasculature in the endoglin heterozygous mouse brain.
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-beta receptor 1 (T beta R1) 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.
authors.affiliation: Department of Anesthesia and Perioperative Care, UC San Francisco, California 94110, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Yong Qin
authors.initials: YQ
authors.lastname: Wu
authors.forename: Madeleine
authors.initials: M
authors.lastname: Huey
authors.forename: Helen M
authors.initials: HM
authors.lastname: Arthur
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Marchuk
authors.forename: Tomoki
authors.initials: T
authors.lastname: Hashimoto
authors.forename: William L
authors.initials: WL
authors.lastname: Young
authors.forename: Guo-Yuan
authors.initials: GY
authors.lastname: Yang
mesh_terms: D000818:Animals; D015703:Antigens, CD; D002560:Cerebrovascular Circulation; D000071063:Endoglin; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; C467484:VEGFA protein, human; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I