Atherosclerosis is the major cause of death and disability in the United States. Physiological laminar flow in blood vessels has been shown to be atheroprotective, which is, in part, mediated by laminar flow-stimulated endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production from endothelial cells (EC). The molecular mechanisms by which laminar flow mediates eNOS activation and atheroprotective effects are not clear but likely relate to mechanical signaling transduction. In a proteomic search for potential mediators of eNOS activation, we identified vascular endothelial growth factor receptor 2 (VEGFR2) as being involved in laminar flow-induced eNOS activation. The published data from my laboratory have demonstrated that laminar flow-induced eNOS phosphorylation and activation depends solely upon VEGFR2 activation, since highly specific VEGFR2 kinase inhibitors completely abolish laminar flow-mediated eNOS activation and NO production in vitro and vasodilation in vivo. Importantly, VEGFR2 activation by laminar flow occurs in a ligand-independent manner. It is well known that VEGF as a natural ligand stimulates VEGFR2 and induces an inflammatory response partially via NO production in EC. Conversely, emerging evidence from my laboratory support a new role of VEGFR2 in the anti-inflammatory effect of laminar flow via NO dependent and independent mechanisms. My central hypothesis is that specific activation of VEGFR2 confers the anti-inflammatory effect of laminar flow through assembly and activation of a distinct signaling module via docking protein Gab1. This global hypothesis will be tested via the following three specific aims:
Aim 1. To study phosphorylation and function of tyrosine residues in VEGFR2 activated by laminar flow.
Aim 2. To determine the role of Gab1 in VEGFR2 signaling and function induced by laminar flow.
Aim 3. To examine the role of VEGFR2 in the anti-inflammatory effect of laminar flow using an ex vivo organ culture system of intact aorta. These studies proposed herein will provide a framework to begin defining a mechanistic pathway linking mechanical force application to VEGFR2 activation, eNOS activation and proinflammatory gene inhibition. In this pathway, VEGFR2 may emerge as a central mediator for laminar flow atheroprotective effects, which will provide new insight into the prevention of atherosclerotic vascular disease. ? ?
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