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

Abstract

Brain arteriovenous malformations (BAVMs) are a rare but potentially devastating hemorrhagic disease. Transforming growth factor-␤ signaling is required for proper vessel development, and defective transforming growth factor-␤ superfamily signaling has been implicated in BAVM pathogenesis. We hypothesized that expression of the transforming growth factor-␤ activating integrin, ␣v␤8, is reduced in BAVMs and that decreased ␤8 expression leads to defective neoangiogenesis. We determined that ␤8 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 ␤8 immunostaining in BAVM tissue. These three lines of evidence from human studies and a mouse model suggest that reduced expression of integrin ␤8 may be involved in the pathogenesis of sporadic BAVMs. (Am J Pathol

Transcription of the Transforming Growth Factor β Activating Integrin β8 Subunit Is Regulated by SP3, AP-1, and the p38 Pathway

“…Previous studies have demonstrated important roles for AP-1, p38, and TGF-␤ in normal epithelial-mesenchymal homeostasis and wound healing of the skin and lung (23,47,84,85). We have also shown that integrin ␤8 regulates epithelial-mesenchymal and endothelial-mesenchymal homeostasis in the airway and brain, respectively (1,2,15,17). Here we show a direct link between p38, AP-1, and TGF-␤ in these processes via regulation of integrin ␤8 expression.…”

“…Interestingly, a genetic variant in the ITGB8 locus has recently been found to correlate with risk of brain arteriovenous malformation development and the at-risk brain arteriovenous malformation variant was associated with reduced ␤8 protein expression (2). Here we describe the first characterization of the promoter and elements that regulate ITGB8 expression and place it under the control of p38, a stress-activated and proinflammatory protein.…”

“…In adult tissues, increased expression of ␤8 has been shown in airway fibroblasts in lung tissue from chronic obstructive pulmonary disease patients and its expression is reduced in adenocarcinomas of the lung and in perivascular astrocytes in brain arteriovenous malformations (1,2,4). ITGB8 has been found to be increased in BRCA-1 positive breast cancers and has been identified as part of a six-gene expression signature predicting lung metastasis from breast cancer (3,22).…”

Interleukin-1β Induces Increased Transcriptional Activation of the Transforming Growth Factor-β-activating Integrin Subunit β8 through Altering Chromatin Architecture

“…Decreased expression of ␣v␤8 has been found in brain arteriovenous malformations, and increased expression of ␣v␤8 has been found in airway fibroblasts from patients with fibrotic remodeling of their airway wall, one of the cardinal features of chronic obstructive pulmonary disease (COPD) (5,15,16). ITGB8 is a direct transcriptional target of IL-1␤, a crucial proinflammatory cytokine implicated in brain arteriovenous malformation and COPD pathogenesis (5,15,16).…”

Protein Tyrosine Phosphatase-PEST and β8 Integrin Regulate Spatiotemporal Patterns of RhoGDI1 Activation in Migrating Cells

“…During brain development, ␣v␤8 integrin in neural cells promotes latent TGF␤ activation and signaling to control angiogenesis and formation of the blood-brain barrier (15)(16)(17)(18)(19)(20). Single nucleotide polymorphisms in the human ␤8 integrin (ITGB8) gene that diminish protein expression have been identified in patients with brain vascular malformations (21). ITGB8 expression levels are upregulated in nervous system malignancies, including glioblastoma (22,23) and peripheral nerve sheath tumors (24).…”