ICAM-1 governs angiogenesis and endothelial redox status

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DESCRIPTION (provided by applicant): Stimulation of angiogenesis involves the transition of endothelial cells from a quiescent to mitogenic and pro-migratory phenotype. Coordinate regulation of endothelial cell motility is an integral process in this phenomenon. However, specific molecular mechanisms responsible for directional migration of endothelial cells remain poorly characterized. VEGF(164) is a potent mediator of endothelial cell migration through activation of various cellular pathways including PI3K, Akt, and eNOS. Recent studies demonstrate that VEGF(164) stimulation increases adhesion molecule expression, such as intercellular adhesion molecule-1 (ICAM-1) expression, which may participate in VEGF mediated endothelial cell migration. However, there is a paucity of information detailing mechanisms of adhesion molecule regulation of angiogenesis. Therefore, this proposal will investigate the hypothesis that ICAM-1 governs VEGF(164) angiogenic activity by negatively regulating glutamate cysteine ligase (GCL-C) and subsequent glutathione (GSH) redox regulation of PTEN phosphatase, and modulates endothelial NOS activity and intracellular localization. This hypothesis will be examined by the following specific aims: 1) determine how ICAM-1 modulates GCL-C function and examine how GSH affects VEGF(164) ROS production, 2) determine how ICAM-1 governs eNOS cellular localization and activity in response to VEGF(164) stimulation, and 3) determine how increased intracellular levels of GSH affect PTEN regulation of VEGF(164) signaling. Data accumulated from these aims will provide unique insight into the role of ICAM-1 in controlling endothelial glutathione metabolism, eNOS activity and bioavailability, and PTEN activity during VEGF(164) mediated angiogenesis and endothelial cell chemotaxis. Completion of this project will significantly advance our understanding of specific mechanisms by which inflammatory adhesion molecules regulate angiogenesis and identify new targets for therapeutic angiogenic intervention.