Reduced Expression of Integrin αvβ8 Is Associated with Brain Arteriovenous Malformation Pathogenesis

Center of Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110, USA.
American Journal Of Pathology (Impact Factor: 4.59). 12/2009; 176(2):1018-27. DOI: 10.2353/ajpath.2010.090453
Source: PubMed


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.

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Available from: Guo-Yuan Yang, Feb 11, 2014
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    • "Two integrins that via heterodimerization form a fibronectin receptor (and an activating integrin for TGFβ signaling), Itgv and Itgβ8, were also down-regulated. Conditional deletion of Itgαv in radial glia and neurons causes cerebral hemorrhage [114] while reduced expression of αvβ8 integrin is associated with arteriorvenous malformations [115]. Other down-regulated genes encoding adhesion molecules were: Jam3, a tight-junction protein essential for maintaining the integrity of the cerebrovascular endothelium [116]; Cdh6, which is expressed in the VZ where it may serve to assign the cortico-striatal boundary [117]; two additional IGSFM genes, Boc and Cdon, that are evident in the VZ, where they function in Sonic Hedgehog signaling and are implicated in forms of holoprosencephaly [118,119]. "
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    • "αvβ8 integrin is a receptor for latent TGFβ and loss of integrin expression leads to diminished TGFβ activation and signaling in the adult brain (Mobley et al., 2009; Su et al., 2010). Various genetic studies have also linked αvβ8 integrin to TGFβs during embryonic brain development (Mu et al., 2008). "
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