Nox1 and Nox4 Containing Oxidases are Required for PDGF-induced Migration of

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DESCRIPTION (provided by applicant): Migration of vascular smooth muscle cells (VSMCs) plays an important role in cardiovascular disease progression. The migration of VSMCs is associated with atherosclerosis and restenosis after angioplasty due to increased neointima formation. Recent studies demonstrate that platelet derived growth factor (PDGF) stimulation promotes ROS formation and migration of VSMCs. ROS act as signaling molecules in cellular pathways that modulate migration, but the source of these ROS, the mechanisms regulating their production, and their downstream targets remain unclear. Here I propose a mechanism by which both Nox1 and Nox4 NADPH oxidases are required for VSMC migration. I hypothesize that PDGF-induced migration in VSMCs requires basal Nox4 activity and Rac-mediated stimulation of Nox1 to modulate focal adhesion dynamics and the actin cytoskeleton. In this proposal, I will evaluate this hypothesis via three aims. In the first aim, I will determine the mechanism by which PDGF activates Rac to stimulate Nox1 and modulate redox sensitive signaling pathways that alter actin polymerization. In aim 2, I will evaluate the role of Nox4 expression and activity on Rho expression and Rho-mediated focal adhesion turnover in VSMCs. The third and final aim will test some of these concepts in vivo by examining the role of Nox4 in neoinitmal formation. Understanding the mechanism by which PDGF induces VSMC migration is very important to developing therapeutic strategies to combat cardiovascular disease.