Mechanism of SSH1L Phosphatase Activation in VSMC: Role in Vascular Pathology

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Vascular smooth muscle cell (VSMC) migration, which in vivo is primarily the consequence of activation of the PDGF-p receptor by platelet-derived growth factor (PDGF), contributes to post-angioplasty restenosis and atherosclerosis. Although cell migration involves different mechanisms in different cell types and tissue environments, it is a universal process that in all cases involves remodelling of actin cytoskeleton. Cofilin is a protein that regulates actin dynamics by stimulating rapid turnover of actin filaments. Cofilin is activated by dephosphorylation by the Slingshot phosphatase SSH1L. However, the mechanisms leading to SSHIL activation are unknown. Our preliminary data strongly suggest that NADPH oxidase-1 (Noxl)-derived reactive oxygen species (ROS) participate in SSH1L activation. Based on these observations, three specific aims will be investigated. First, the role of Nox 1-derived ROS in SSH1L phosphatase activation or changes in subcellular localization will be determined. Second, we will characterize the upstream signaling pathways responsible for ROS-induced SSHIL activation in VSMC; particularly, we will focus on the participation of protein partners which regulate SSHIL activity. Finally, the role of SSH1L in VSMC migration during neointimal formation will be investigated. These studies will provide important insight into the mechanisms controlling vascular smooth muscle cell migration, and may help to identify new therapeutic targets for vascular disease. In summary, in this proposal we will explore the role of ROS-dependent mechanisms of SSHIL activation by PDGF at the molecular level in VSMC, and we will evaluate the impact of this activation pathway in vivo. These studies will help to identify potential therapeutic targets for pathologies such as atherosclerosis and restenosis that involve dysregulation of VSMC migration.