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(American Journal of Pathology. 2005;166:1883-1894.)
© 2005 American Society for Investigative Pathology

Integrin {alpha}vß8-Mediated Activation of Transforming Growth Factor-ß by Perivascular Astrocytes

An Angiogenic Control Switch

Stephanie Cambier*, Stephanie Gline*, Dezhi Mu*, Rodney Collins*, Jun Araya*, Gregory Dolganov{dagger}, Steven Einheber{ddagger}, Nancy Boudreau§ and Stephen L. Nishimura*

From the Departments of Pathology,* Medicine,{dagger} and Surgery,§ University of California San Francisco, San Francisco, California; and the School of Heath Sciences, Hunter College,{ddagger} New York, New York

Brain hemorrhage is a severe complication of both neoplastic and nonneoplastic brain disease. Mice deficient in the {alpha}vß8 integrin display defective brain vessel formation resulting in hemorrhage and perinatal death, but the mechanism of brain hemorrhage is unknown. Because the {alpha}vß8 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)-ß by astrocytes influences endothelial cell function. Thus, we identified the integrin {alpha}vß8 in human perivascular glial cell processes surrounding developing blood vessels. Human astrocytic {alpha}vß8 was a major cell surface receptor for latent TGF-ß, and {alpha}vß8-dependent activation of TGF-ß was the major mechanism of TGF-ß activation in primary cultures of astrocytes or freshly dissociated fetal brain cells. This activation of TGF-ß 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 {alpha}vß8 acts as a central regulator of brain vessel homeostasis through regulation of TGF-ß activation and expression of TGF-ß-responsive genes that promote vessel differentiation and stabilization, most notably plasminogen activator inhibitor-1 and thrombospondin-1.




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