Integrin αvβ8-mediated activation of transforming growth factor-β by perivascular astrocytes: an angiogenic control switch

S Cambier, S Gline, D Mu, R Collins, J Araya… - The American journal of …, 2005 - Elsevier
S Cambier, S Gline, D Mu, R Collins, J Araya, G Dolganov, S Einheber, N Boudreau…
The American journal of pathology, 2005Elsevier
Brain hemorrhage is a severe complication of both neoplastic and nonneoplastic brain
disease. Mice deficient in the αvβ8 integrin display defective brain vessel formation resulting
in hemorrhage and perinatal death, but the mechanism of brain hemorrhage is unknown.
Because the αvβ8 integrin is expressed by astrocytes and not expressed by endothelium,
paracrine interactions between astrocytes and endothelial cells could contribute to the
maintenance of brain vessel integrity. We have investigated the mechanisms underlying …
Brain hemorrhage is a severe complication of both neoplastic and nonneoplastic brain disease. Mice deficient in the αvβ8 integrin display defective brain vessel formation resulting in hemorrhage and perinatal death, but the mechanism of brain hemorrhage is unknown. Because the αvβ8 integrin is expressed by astrocytes and not expressed by endothelium, paracrine interactions between astrocytes and endothelial cells could contribute to the maintenance of brain vessel integrity. We have investigated the mechanisms underlying astrocytic-endothelial paracrine signaling and have found that integrin-mediated activation of transforming growth factor (TGF)-β by astrocytes influences endothelial cell function. Thus, we identified the integrin αvβ8 in human perivascular glial cell processes surrounding developing blood vessels. Human astrocytic αvβ8 was a major cell surface receptor for latent TGF-β, and αvβ8-dependent activation of TGF-β was the major mechanism of TGF-β activation in primary cultures of astrocytes or freshly dissociated fetal brain cells. This activation of TGF-β was sufficient to inhibit endothelial migration in fibrin gels and to alter expression of genes affecting proteolytic and angiogenic pathways. Taken together, our data suggest that astrocytic αvβ8 acts as a central regulator of brain vessel homeostasis through regulation of TGF-β activation and expression of TGF-β-responsive genes that promote vessel differentiation and stabilization, most notably plasminogen activator inhibitor-1 and thrombospondin-1.
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