Absence of the αvβ3 Integrin Dictates the Time-Course of Angiogenesis in the Hypoxic Central Nervous System: Accelerated Endothelial Proliferation Correlates with Compensatory Increases in α5β1 Integrin Expression

Cerebral angiogenesis is an important adaptive response to hypoxia. As the alpha v beta 3 integrin is induced on angiogenic vessels in the ischemic central nervous system (CNS), and the suggested angiogenic role for this integrin in other systems, it is important to determine whether the alpha v beta 3 integrin is an important mediator of cerebral angiogenesis. alpha v beta 3 integrin expression was examined in a model of cerebral hypoxia, in which mice were subject to hypoxia (8% O(2)) for 0, 4, 7, or 14 days. Immunofluorescence and western blot analysis revealed that in the hypoxic CNS, alpha v beta 3 integrin was strongly induced on angiogenic brain endothelial cells (BEC), along with its ligand vitronectin. In the hypoxia model, beta 3 integrin-null mice showed no obvious defect in cerebral angiogenesis. However, early in the angiogenic process, BEC in these mice showed an increased mitotic index that correlated closely with increased alpha 5 integrin expression. In vitro experiments confirmed alpha 5 integrin upregulation on beta 3 integrin-null BEC, which also correlated with increased BEC proliferation on fibronectin. These studies confirm hypoxic induction of alpha v beta 3 integrin on angiogenic vessels, but suggest distinct roles for the BEC integrins alpha v beta 3 and alpha 5 beta 1 in cerebral angiogenesis, with alpha v beta 3 having a nonessential role, and alpha 5 beta 1 promoting BEC proliferation.