Role of PTEN in Vascular Lesion Formation

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DESCRIPTION (provided by applicant): Restenosis is characterized by smooth muscle cell (SMC) accumulation in the arterial intima through dedifferentiation, migration, and proliferation of medial-derived SMC. An inflammatory response, characterized by bone marrow-derived and/or circulating inflammatory and progenitor cell recruitment to the injured vessel, also contributes to restenosis. Several chemokines, including MCP-1/JE, SDF-1a, IL-6, and CXCL1/KC, are rapidly induced in SMC following injury and participate in the remodeling process through the recruitment of inflammatory and vascular progenitor cells. Some of these factors have also been shown to directly affect the biological function of the SMC itself placing the SMC as both a mediator and an effector of the injury response. However, the underlying molecular programs activated in SMC in response to injury are not clearly defined. Our previous work indicates SMC-specific PTEN inactivation, a negative regulator of PI3-kinase signaling, is an early trigger driving vascular lesion formation. We generated inducible SMC-specific PTEN mutant mice (PTEN iKO) and found that, compared to controls, PTEN iKO mice exhibit significant reductions of total PTEN in major vessels with accompanying increased phosphoAkt levels and enhanced neointima formation following carotid arterial injury. PTEN-deficient SMC in vitro exhibit an autocrine growth phenotype under basal conditions and express a cytokine/chemokine profile similar to what is observed in SMC following experimental injury. Preliminary data show that PTEN depletion activates the transcription factors, NF?B and HIF-1a; inhibition of NF?B or HIF-1a blocked the upregulation of specific chemokines mediated by PTEN depletion. On the other hand, our preliminary data suggest that activation of the nuclear receptor, PPAR?, in SMC upregulates PTEN, therefore our studies will examine the ability of PPAR? activation to inhibit SMC proliferation and regulate anti-inflammatory responses through the upregulation of SMC PTEN. Overall, our preliminary data provide evidence that an alteration in SMC PTEN signaling serves as a key initiating determinant driving pathological vascular remodeling through the production of a family of chemoattractants that recruit inflammatory/progenitor cells through a paracrine mechanism and promote an autocrine SMC hyperplastic response. Therefore, restoration of SMC PTEN signaling is anticipated to reverse the cascade of events brought on by vascular injury. We will determine the consequences and mechanism of action of PTEN loss on SMC production of progenitor/inflammatory cell mediators in cultured PTEN null SMC and assess the relative contribution of SMC-specific deletion of PTEN in mice on chemokine-induced SMC hyperplasia and recruitment of progenitor and inflammatory cells during neointima formation following experimental vascular injury in Aim One. In Aim Two, we will determine the role of PPAR? agonists on the upregulation of PTEN and biological functions of SMC and determine the role of PTEN regulation in mediating the protective effects of PPAR? agonists against the development of injury-induced vascular remodeling. PUBLIC HEALTH RELEVANCE: Complications of heart disease remain the leading cause of death in Western societies. While angioplasty/stent deployment and graft transplantations have been widely used for the treatment of atherosclerosis, a significant proportion of these procedures fail due to post-procedure restenosis, characterized by significant cell growth and inflammatory responses that lead to vessel blockage. Therefore, a great deal of effort has gone into defining the underlying mechanisms regulating these processes to reduce post-intervention vascular occlusion. Our studies are designed to test the role and mechanisms of action of a protein, PTEN, expressed by vascular cells in actively blocking the expression of a family of chemokines that otherwise promote vascular cell growth and an inflammatory response following vascular interventions.