title: Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain.
abstract: OBJECTIVE
  Vessels in brain arteriovenous malformations are prone to rupture. The underlying pathogenesis is not clear. Hereditary hemorrhagic telangiectasia type 2 patients with activin receptor-like kinase 1 (Alk1) mutation have a higher incidence of brain arteriovenous malformation than the general population. We tested the hypothesis that vascular endothelial growth factor impairs vascular integrity in the Alk1-deficient brain through reduction of mural cell coverage.
  
  
  RESULTS
  Adult Alk1(1f/2f) mice (loxP sites flanking exons 4-6) and wild-type mice were injected with 2×10(7) PFU adenovious-cre recombinase and 2×10(9) genome copies of adeno-associated virus-vascular endothelial growth factor to induce focal homozygous Alk1 deletion (in Alk1(1f/2f) mice) and angiogenesis. Brain vessels were analyzed 8 weeks later. Compared with wild-type mice, the Alk1-deficient brain had more fibrin (99±30×10(3) pixels/mm(2) versus 40±13×10(3); P=0.001), iron deposition (508±506 pixels/mm(2) versus 6±49; P=0.04), and Iba1(+) microglia/macrophage infiltration (888±420 Iba1(+) cells/mm(2) versus 240±104 Iba1(+); P=0.001) after vascular endothelial growth factor stimulation. In the angiogenic foci, the Alk1-deficient brain had more α-smooth muscle actin negative vessels (52±9% versus 12±7%, P<0.001), fewer vascular-associated pericytes (503±179/mm(2) versus 931±115, P<0.001), and reduced platelet-derived growth factor receptor-β expression.
  
  
  CONCLUSIONS
  Reduction of mural cell coverage in response to vascular endothelial growth factor stimulation is a potential mechanism for the impairment of vessel wall integrity in hereditary hemorrhagic telangiectasia type 2-associated brain arteriovenous malformation.
authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, CA 94110, USA
authors.forename: Wanqiu
authors.initials: W
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Guo
authors.forename: Espen J
authors.initials: EJ
authors.lastname: Walker
authors.forename: Fanxia
authors.initials: F
authors.lastname: Shen
authors.forename: Kristine
authors.initials: K
authors.lastname: Jun
authors.forename: S Paul
authors.initials: SP
authors.lastname: Oh
authors.forename: Vincent
authors.initials: V
authors.lastname: Degos
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lawton
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Davalos
authors.forename: Katerina
authors.initials: K
authors.lastname: Akassoglou
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Nelson
authors.forename: John
authors.initials: J
authors.lastname: Pile-Spellman
authors.forename: Hua
authors.initials: H
authors.lastname: Su
authors.forename: William L
authors.initials: WL
authors.lastname: Young
mesh_terms: D000199:Actins / Q000378:metabolism; D030201:Activin Receptors, Type I / Q000172:deficiency* / Q000235:genetics; D030301:Activin Receptors, Type II; D000818:Animals; D000077214:Becaplermin; D001808:Blood Vessels / Q000201:enzymology* / Q000473:pathology; D001921:Brain / Q000098:blood supply*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005337:Fibrin / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007501:Iron / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D020286:Pericytes / Q000201:enzymology* / Q000473:pathology; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; C544013:alpha-smooth muscle actin, mouse; D000077214:Becaplermin; D005337:Fibrin; D007501:Iron; D020797:Receptor, Platelet-Derived Growth Factor beta; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse