Reduced expression of integrin alphavbeta8 is associated with brain arteriovenous malformation pathogenesis.
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.
Su
Hua
H
Center of Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110, USA.
Kim
Helen
H
Pawlikowska
Ludmila
L
Kitamura
Hideya
H
Shen
Fanxia
F
Cambier
Stephanie
S
Markovics
Jennifer
J
Lawton
Michael T
MT
Sidney
Stephen
S
Bollen
Andrew W
AW
Kwok
Pui-Yan
PY
Reichardt
Louis
L
Young
William L
WL
Yang
Guo-Yuan
GY
Nishimura
Stephen L
SL
D000818:Animals; D001164:Arteriovenous Fistula / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D015536:Down-Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D016023:Integrins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D002538:Intracranial Arteriovenous Malformations / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016023:Integrins; D016212:Transforming Growth Factor beta; C403414:integrin alphavbeta8