title: Integrin β8 Deletion Enhances Vascular Dysplasia and Hemorrhage in the Brain of Adult Alk1 Heterozygous Mice.
abstract: Brain arteriovenous malformation (bAVM), characterized by tangled dysplastic vessels, is an important cause of intracranial hemorrhage in young adults, and its pathogenesis and progression are not fully understood. Patients with haploinsufficiency of transforming growth factor-β (TGF-β) receptors, activin receptor-like kinase 1 (ALK1) or endoglin (ENG) have a higher incidence of bAVM than the general population. However, bAVM does not develop effectively in mice with the same haploinsufficiency. The expression of integrin β8 subunit (ITGB8), another member in the TGF-β superfamily, is reduced in sporadic human bAVM. Brain angiogenic stimulation results at the capillary level of vascular malformation in adult Alk1 haploinsufficient (Alk1+/-) mice. We hypothesized that deletion of Itgb8 enhances bAVM development in adult Alk1+/-mice. An adenoviral vector expressing Cre recombinase (Ad-Cre) was co-injected with an adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF) into the brain of Alk1+/-;Itgb8-floxed mice to induce focal Itgb8 gene deletion and angiogenesis. We showed that compared with Alk+/-mice (4.75 ± 1.38/mm2), the Alk1+/-;Itgb8-deficient mice had more dysplastic vessels in the angiogenic foci (7.14 ± 0.68/mm2, P = 0.003). More severe hemorrhage was associated with dysplastic vessels in the brain of Itgb8-deleted Alk1+/-, as evidenced by larger Prussian blue-positive areas (1278 ± 373 pixels/mm2vs. Alk1+/-: 320 ± 104 pixels/mm2; P = 0.028). These data indicate that both Itgb8 and Alk1 are important in maintaining normal cerebral angiogenesis in response to VEGF. Itgb8 deficiency enhances the formation of dysplastic vessels and hemorrhage in Alk1+/-mice.
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Avenue, Box 1363, San Francisco, CA, 94143, USA.|Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Avenue, Box 1363, San Francisco, CA, 94143, USA.
authors.forename: Fanxia
authors.initials: F
authors.lastname: Shen
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Avenue, Box 1363, San Francisco, CA, 94143, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Jun
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Avenue, Box 1363, San Francisco, CA, 94143, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Bao
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Avenue, Box 1363, San Francisco, CA, 94143, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Kuo
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Avenue, Box 1363, San Francisco, CA, 94143, USA.|Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.|Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Young
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nishimura
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Avenue, Box 1363, San Francisco, CA, 94143, USA. hua.su@ucsf.edu.
authors.forename: Hua
authors.initials: H
authors.lastname: Su
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D030301:Activin Receptors, Type II; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism*; D020300:Intracranial Hemorrhages / Q000235:genetics* / Q000473:pathology*; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D039641:Integrin beta Chains; D042461:Vascular Endothelial Growth Factor A; C094865:integrin beta8; D049452:Green Fluorescent Proteins; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse
keywords: Activin receptor-like kinase 1; Brain arteriovenous malformations; Brain hemorrhage; Integrin β8; Mouse model