Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 166, Issue 6, Pages 1883-1894Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S0002-9440(10)62497-2
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Funding
- NHLBI NIH HHS [K02 HL070622, HL70622, HL63993, R01 HL063993] Funding Source: Medline
- NINDS NIH HHS [NS44655] Funding Source: Medline
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Brain hemorrhage is a severe complication of both neoplastic and nonneoplastic brain disease. Mice deficient in the alpha v beta 8 integrin display defective brain vessel formation resulting in hemorrhage and perinatal death, but the mechanism of brain hemorrhage is unknown. Because the alpha v beta 8 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)-beta by astrocytes; influences endothelial cell function. Thus, we identified the integrin alpha v beta 8 in human perivascular glial cell processes surrounding developing blood vessels. Human astrocytic alpha v beta 8 was a major cell surface receptor for latent TGF-beta, and alpha v beta 8-dependent activation of TGF-beta was the major mechanism of TGF-beta activation in primary cultures of astrocytes or freshly dissociated fetal brain cells. This activation of TGF-beta 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 v beta 8 acts as a central regulator of brain vessel homeostasis through regulation of TGF-beta activation and expression of TGF-beta-responsive genes that promote vessel differentiation and stabilization, most notably plasminogen activator inhibitor-1 and thrombospondin-1.
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