SELECTINS ROLE IN VASCULAR INJURY IN GENE-TARGETED

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DESCRIPTION: Restenosis after percutaneous interventions remain a major challenge, occurring in 20-40 percent after balloon angioplasty or stents. Neointima formation is an important mechanism and represents a complex healing process that includes adhesive interactions between inflammatory cells and the vessel wall. The selectin adhesion molecules participate in the early steps of leukocyte recruitment but their exact role after vascular injury is incompletely understood. Accordingly, the primary goal of this proposal is to understand the role of E- and P-selectin and their interactions on neutrophil and macrophage/foam cell accumulation and neointimal growth following arterial injury using gene-targeted mice deficient in expression of apoE plus P-selectin and/or E-selectin and monoclonal antibodies directed against E- and/or P-selectin. SpecificAim1 will test the hypothesis that elimination of P-selectin and/or E-selectin by gene-targeting limits leukocyte entry and accumulation and neointima formation following carotid denudation injury in apoE deficient mice. Histomorphometry and detailed immunohistochemical analysis will be utilized together with serial MRI imaging. Although P-selectin has recently been shown to occupy a preeminent role in regulating leukocyte behavior in a mouse model of inflammation, both discrete functional differences and similar/overlapping functions are described for E- and Pselectin. Accordingly, Specific Aim 2 will test the hypothesis that transient inhibition of E-selectin, P-selectin or both using blocking monoclonal antibodies each or together limit leukocyte entry and accumulation and neointima formation following carotid denudation injury in gene-targeted mice deficient in expression of apoE. To address the specific mechanism(s) by which P-selectin is anticipated to exert its protective effect on vascular repair after wire denudation injury, bone marrow transplantation will be performed in aim 3. Specific Aim 3 will test the hypothesis that platelet P-selectin is responsible for the protective effect of P-selectin deletion/blockade on leukocyte accumulation and neointima formation following carotid denudation injury in gene-targeted mice deficient in expression of apoE. Taken together, these studies will provide new insights into the role(s) of the selectins in inflammatory cell trafficking and neointimal growth after vascular injury in atherosclerosis-prone apoE-deficient mice. In addition, these studies will open new avenues to potential therapeutic strategies to limit neointimal growth after vascular injury.