Diabetes mellitus is a major risk factor for cardiovascular morbidity and mortality. Diabetic macrovascular disease is characterized by accelerated atherosclerosis, a propensity for acute thrombotic events, and a higher risk of clinical restenosis following percutaneous coronary intervention due to increased development of intimal hyperplasia after vascular injury. However, the pathogenesis of diabetic macrovascular disease is incompletely understood. Diabetes has many features of both a chronic inflammatory and pro-thrombotic state. Platelet-leukocyte interactions may play an important role in both thrombotic and inflammatory states and may serve as a crucial link between these systems and the development of vascular disease. This grant application is designed to test the hypothesis that platelets contribute to enhanced intimal hyperplasia in diabetes via P-selectin-mediated recruitment of both mature leukocytes and progenitor cells to sites of vascular damage. Furthermore, we propose that platelet mediated recruitment of exogenous angioblasts from normoglycemic donors could be used to enhance re-endothelialization at sites of injury and reduce the development of intimal hyperplasia in diabetic mice.
The specific aims are: (1) To determine the role of platelet-leukocyte interactions in the development of intimal hyperplasia in mice with type I diabetes. (2) To determine the role of platelet recruitment of circulating progenitor cell in the development of intimal hyperplasia in mice with type I diabetes. (3) To determine the role of P-selectin in the development of intimal hyperplasia after vascular injury in mice with type I diabetes. (4) To determine whether administration of exogenous angioblasts will reduce the development of intimal hyperplasia in mice with type I diabetes. (5) To establish an in vitro assay to measure the effects of diabetes on platelet-progenitor cell interactions. Our findings should advance understanding of how diabetes alters the response to arterial injury and may direct therapeutic strategies that could be used to prevent restenosis in diabetic patients. Moreover, our results may have broad implications for the treatment and prevent of accelerated atherosclerosis and thrombosis in diabetes.
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