Reduced Expression of Integrin {alpha} v {beta} 8 Is Associated with Brain Arteriovenous Malformation Pathogenesis

Hua Su
American Journal of Pathology, 2009

Brain arteriovenous malformations (BAVMs) are a rare but potentially devastating hemorrhagic disease. Transforming growth factor-ß signaling is required for proper vessel development, and defective transforming growth factor-ß superfamily signaling has been implicated in BAVM pathogenesis. We hypothesized that expression of the transforming growth factor-ß activating integrin, avß8, is reduced in BAVMs and that decreased ß8 expression leads to defective neoangiogenesis. We determined that ß8 protein expression in perivascular astrocytes was reduced in human BAVM lesional tissue compared with controls and that the angiogenic response to focal vascular endothelial growth factor stimulation in adult mouse brains with local Cre-mediated deletion of itgb8 and smad4 led to vascular dysplasia in newly formed blood vessels. In addition, common genetic variants in ITGB8 were associated with BAVM susceptibility, and ITGB8 genotypes associated with increased risk of BAVMs correlated with decreased ß8 immunostaining in BAVM tissue. These three lines of evidence from human studies and a mouse model suggest that reduced expression of integrin ß8 may be involved in the pathogenesis of sporadic BAVMs.

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American Journal of Pathology