title: Arteriovenous malformation in the adult mouse brain resembling the human disease.
abstract: OBJECTIVE
  Brain arteriovenous malformations (bAVMs) are an important cause of hemorrhagic stroke. The underlying mechanisms are not clear. No animal model for adult bAVM is available for mechanistic exploration. Patients with hereditary hemorrhagic telangiectasia type 2 (HHT2) with activin receptor-like kinase 1 (ALK1; ACVRL1) mutations have a higher incidence of bAVM than the general population. We tested the hypothesis that vascular endothelial growth factor (VEGF) stimulation with regional homozygous deletion of Alk1 induces severe dysplasia in the adult mouse brain, akin to human bAVM.
  
  
  METHODS
  Alk1(2f/2f) (exons 4-6 flanked by loxP sites) and wild-type (WT) mice (8-10 weeks old) were injected with adenoviral vector expressing Cre recombinase (Ad-Cre; 2 × 10(7) plaque forming units [PFU]) and adeno-associated viral vectors expressing VEGF (AAV-VEGF; 2 × 10(9) genome copies) into the basal ganglia. At 8 weeks, blood vessels were analyzed.
  
  
  RESULTS
  Gross vascular irregularities were seen in Alk1(2f/2f) mouse brain injected with Ad-Cre and AAV-VEGF. The vessels were markedly enlarged with abnormal patterning resembling aspects of the human bAVM phenotype, displayed altered expression of the arterial and venous markers (EphB4 and Jagged-1), and showed evidence of arteriovenous shunting. Vascular irregularities were not seen in similarly treated WT mice.
  
  
  CONCLUSIONS
  Our data indicate that postnatal, adult formation of the human disease, bAVM, is possible, and that both genetic mutation and angiogenic stimulation are necessary for lesion development. Our work not only provides a testable adult mouse bAVM model for the first time, but also suggests that specific medical therapy can be developed to slow bAVM growth and potentially stabilize the rupture-prone abnormal vasculature.
authors: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110, USA.
authors: Espen J
authors: EJ
authors: Walker
authors: Hua
authors: H
authors: Su
authors: Fanxia
authors: F
authors: Shen
authors: Eun-Jung
authors: EJ
authors: Choi
authors: S Paul
authors: SP
authors: Oh
authors: Grant
authors: G
authors: Chen
authors: Michael T
authors: MT
authors: Lawton
authors: Helen
authors: H
authors: Kim
authors: Yongmei
authors: Y
authors: Chen
authors: Wanqiu
authors: W
authors: Chen
authors: William L
authors: WL
authors: Young
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics; D000818:Animals; D001165:Arteriovenous Malformations / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000139:chemically induced; D036224:Receptor, EphB4 / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D014161:Transduction, Genetic / Q000379:methods; D042461:Vascular Endothelial Growth Factor A / Q000009:adverse effects
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D036224:Receptor, EphB4; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II