This research proposal will focus on the biological role of protein kinase C (PKC) in alpha-v integrin-mediated endothelial cell (EC) migration and angiogenesis. Preliminary data suggests that two cytokine- dependent pathways of angiogenesis exist and are defined by their dependency on distinct vascular integrins. In vivo angiogenesis in rabbit corneal or chick chorioallantoic membrane models induced by basic fibroblast growth factor or by tumor necrosis factor alpha depended on integrin alpha-v-beta-3, whereas angiogenesis induced by phorbol esters, vascular endothelial growth factor, or transforming growth factor alpha depended on integrin alpha-v-beta-5. Monoclonal antibody antagonists to each integrin selectively blocked one of these pathways, and a cyclic pep tide antagonist of both integrins blocked angiogenesis by each cytokine tested. These pathways are further distinguished by their sensitivity to calphostin C, a PKC inhibitor, that blocked angiogenesis mediated by alpha-v-beta-5, but not alpha-v-beta-3. Therefore to examine the role of PKC in angiogenesis and EC migration, I will first identify the functionally active PKC isoforms in EC exposed to angiogenic cytokines. Second, l will identify the role of PKC in cytokine-induced integrin dependent EC motility.
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