The Role of Integrin Alpha9Beta1 During Angiogenesis Induced by VEGF-A
Integrins are heterodimeric membrane proteins that mediate cell adhesion, migration and proliferation in a number of physiologic processes, including angiogenesis. The integrin α9β1 binds to a number of ligands, including the angiogenic growth factor, VEGF-A, and mediates cell adhesion and proliferation on VEGF-A. Blockade of α9β1 inhibits angiogenesis in the chick and quail chorioallantoic membranes, but the specific cell type(s) in which α9β1 is expressed and the mechanisms by which integrin α9β1 mediates angiogenesis have not been described. The complete knockout of α9 results in lethal chylothoraces between postnatal day 6 and 10, but has no reported deficits of vasculogenesis or developmental angiogenesis. To study the role of α9β1 during pathologic angiogenesis, we generated a mouse in which α9 can be temporally deleted in all tissues following administration of Doxycyline. Administration of Doxycycline after the development of the lymphatics allowed us to define a role for α9β1 during pathologic angiogenesis in adult mice. Deletion of α9β1 inhibited angiogenesis in vivo induced by VEGF-A, but not by bFGF. We determined that α9β1 is expressed on cells which also express the pericyte markers NG2 and PDGFRβ, and not on endothelial cells expressing PECAM. Pericyte-specific deletion of the integrin using an α-Smooth Muscle Actin promoter was sufficient to inhibit angiogenesis in response to VEGF-A due to a failure of pericyte recruitment before endothelial cell recruitment. Taken together, these results indicate that pathologic angiogenesis in response to VEGF-A requires pericyte recruitment before endothelial cell recruitment, and that this pericyte recruitment requires expression of integrin α9β1 on pericytes.