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.

Public Health Relevance

The clear relationship of oxidant stress with restenosis and other vascular disorders in animal models clearly supports the likely importance of this mechanism in clinical cardiology VSMC migration, a mechanism related with the increase of cellular oxidative stress, is implicated in vascular diseases. Therefore, understand the mechanism by which ROS direct VSMC migration will aloud to develop new and more effective therapeutic strategies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Transition Award (R00)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Olive, Michelle
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Montenegro, Marcelo F; Valdivia, Alejandra; Smolensky, Alexander et al. (2015) Nox4-dependent activation of cofilin mediates VSMC reorientation in response to cyclic stretching. Free Radic Biol Med 85:288-94
Valdivia, Alejandra; Duran, Charity; San Martin, Alejandra (2015) The role of Nox-mediated oxidation in the regulation of cytoskeletal dynamics. Curr Pharm Des 21:6009-22
Dikalov, Sergey I; Nazarewicz, Rafal R; Bikineyeva, Alfiya et al. (2014) Nox2-induced production of mitochondrial superoxide in angiotensin II-mediated endothelial oxidative stress and hypertension. Antioxid Redox Signal 20:281-94
Williams, Holly C; San Martin, Alejandra; Adamo, Candace M et al. (2012) Role of coronin 1B in PDGF-induced migration of vascular smooth muscle cells. Circ Res 111:56-65
Lassègue, Bernard; San Martín, Alejandra; Griendling, Kathy K (2012) Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ Res 110:1364-90
Maheswaranathan, Mithunan; Gole, Hope K A; Fernandez, Isabel et al. (2011) Platelet-derived growth factor (PDGF) regulates Slingshot phosphatase activity via Nox1-dependent auto-dephosphorylation of serine 834 in vascular smooth muscle cells. J Biol Chem 286:35430-7
Martin-Garrido, Abel; Brown, David I; Lyle, Alicia N et al. (2011) NADPH oxidase 4 mediates TGF-?-induced smooth muscle ?-actin via p38MAPK and serum response factor. Free Radic Biol Med 50:354-62
San Martín, Alejandra; Griendling, Kathy K (2010) Redox control of vascular smooth muscle migration. Antioxid Redox Signal 12:625-40
Lee, Moo Yeol; San Martin, Alejandra; Mehta, Puja K et al. (2009) Mechanisms of vascular smooth muscle NADPH oxidase 1 (Nox1) contribution to injury-induced neointimal formation. Arterioscler Thromb Vasc Biol 29:480-7