Decreased fibrinolytic activity has been suggested to accelerate the process of arterial atherogenesis by facilitating thrombosis and fibrin deposition within developing atherosclerotic lesions. Type I plasminogen activator inhibitor (PAI-1) is the primary inhibitor of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) and has been found to be increased in a number of clinical conditions generally defined as prothombotic. In preliminary studies, we have demonstrated that PAI-1 overexpressing transgenic mice cross bred with apoE deficient (PAI-1 TG+:apoE null) mice exhibit accelerated atherosclerosis compared to littermate mice while PAI-1 null mice appear protected. On the basis of these studies, we hypothesize that PAI-1 plays a major role in the pathogenesis of atherosclerosis and in the response to vascular injury through its regulation of the plasminogen activation (PA) system with resulting effects on fibrin clearance, monocyte/macrophage recruitment, vascular smooth muscle cell migration and proliferation and extracellular matrix synthesis. To test these hypothesis, we propose to one, confirm our initial findings in pilot studies that PAI-1 TG+_:apoE null mice develop a larger number of atherosclerotic lesions and at earlier time points compared with littermate controls, and characterize the cellular features of these atherosclerotic lesions; two, determine the source of proatherogenic PAI-1 ligands, such as vitronectin, in the development of atherosclerosis; and three, examine the contributions of other components of the PA system, such as tPA and uPA, to the development of atherosclerotic lesions and the response to vascular injury. The goals of this grant are to define the mechanisms by which PAI-1 regulates intimal lesion formation during atherogenesis and following vascular injury. An understanding of these mechanisms may lend insight into the pathophysiology and treatment of vascular diseases.
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