Reduced expression of integrin alphavbeta8 is associated with brain arteriovenous malformation pathogenesis
Document Type
Article
Abstract
Brain arteriovenous malformations (BAVMs) are a rare but potentially devastating hemorrhagic disease. Transforming growth factor-beta signaling is required for proper vessel development, and defective transforming growth factor-beta superfamily signaling has been implicated in BAVM pathogenesis. We hypothesized that expression of the transforming growth factor-beta activating integrin, alphavbeta8, is reduced in BAVMs and that decreased beta8 expression leads to defective neoangiogenesis. We determined that beta8 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 beta8 immunostaining in BAVM tissue. These three lines of evidence from human studies and a mouse model suggest that reduced expression of integrin beta8 may be involved in the pathogenesis of sporadic BAVMs.
Medical Subject Headings
Animals; Arteriovenous Fistula (genetics, metabolism, pathology); Brain (blood supply, metabolism, pathology); Case-Control Studies; Down-Regulation; Genetic Predisposition to Disease; Humans; Integrins (genetics, metabolism, physiology); Intracranial Arteriovenous Malformations (genetics, metabolism, pathology); Linkage Disequilibrium; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neovascularization, Physiologic (genetics); Polymorphism, Single Nucleotide; Transforming Growth Factor beta (metabolism)
Publication Date
12-19-2009
Publication Title
The American journal of pathology
E-ISSN
1525-2191
Volume
176
Issue
2
First Page
1018
Last Page
27
PubMed ID
20019187
Digital Object Identifier (DOI)
10.2353/ajpath.2010.090453
Recommended Citation
Su, Hua; Kim, Helen; Pawlikowska, Ludmila; Kitamura, Hideya; Shen, Fanxia; Cambier, Stephanie; Markovics, Jennifer; Lawton, Michael T.; Sidney, Stephen; Bollen, Andrew W.; Kwok, Pui-Yan; Reichardt, Louis; Young, William L.; Yang, Guo-Yuan; and Nishimura, Stephen L., "Reduced expression of integrin alphavbeta8 is associated with brain arteriovenous malformation pathogenesis" (2009). Neurosurgery. 990.
https://scholar.barrowneuro.org/neurosurgery/990