Integrin β8 Deletion Enhances Vascular Dysplasia and Hemorrhage in the Brain of Adult Alk1 Heterozygous Mice

Transl Stroke Res. 2016 Dec;7(6):488-496. doi: 10.1007/s12975-016-0478-2. Epub 2016 Jun 29.


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/mm2 vs. 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.

Keywords: Activin receptor-like kinase 1; Brain arteriovenous malformations; Brain hemorrhage; Integrin β8; Mouse model.

MeSH terms

  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type I / metabolism*
  • Activin Receptors, Type II
  • Animals
  • Disease Models, Animal
  • Female
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Integrin beta Chains / genetics
  • Integrin beta Chains / metabolism*
  • Intracranial Hemorrhages / genetics*
  • Intracranial Hemorrhages / pathology*
  • Male
  • Malformations of Cortical Development / genetics*
  • Malformations of Cortical Development / pathology*
  • Mice
  • Mice, Transgenic
  • Neovascularization, Pathologic / etiology
  • Neovascularization, Pathologic / genetics
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism


  • Integrin beta Chains
  • Vascular Endothelial Growth Factor A
  • integrin beta8
  • Green Fluorescent Proteins
  • Activin Receptors, Type I
  • Activin Receptors, Type II
  • Acvrl1 protein, mouse