An angiogenic role for the α5β1 integrin in promoting endothelial cell proliferation during cerebral hypoxia

Fibronectin is a critical regulator of vascular modelling, both in development and in the adult. In the hypoxic adult central nervous system (CNS), fibronectin is induced on angiogenic vessels, and endothelial cells show strong induction of the two fibronectin receptors alpha 5 beta 1 and alpha v beta 3 integrins. In a previous study, we found that the alpha v beta 3 integrin is dispensable for hypoxic-induced cerebral angiogenesis, but a role for the endothelial alpha 5 beta 1 integrin was suggested. To directly investigate the role of endothelial alpha 5 integrin in cerebral angiogenesis. wild-type mice and mice lacking alpha 5 integrin expression in endothelial cells (alpha 5-EC-KO) were subject to hypoxia (8% O-2) for 0, 2, 4, 7 or 14 days. Quantification of cerebral vessel density and endothelial-specific proteins claudin-5 and Glut-1 revealed that alpha 5-EC-KO mice displayed an attenuated angiogenic response, which correlated with delayed endothelial proliferation. alpha 5-EC-KO mice showed no defect in the ability to organize a cerebrovascular fibronectin matrix, and no compensatory increase in vascular alpha v beta 3 integrin expression. Consistent with these findings, primary alpha 5KO brain endothelial cells (BEC) in culture exhibited delayed growth and proliferation. Taken together, these studies demonstrate an important angiogenic role for the coo integrin in promoting BEC proliferation in response to cerebral hypoxia. (C) 2012 Elsevier Inc. All rights reserved.