REGULATION OF FIBRINOLYSIS AT SITES OF ARTERIAL INJURY

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Fibrin deposition in response to vascular injury is a key factor in the pathogenesis of acute and chronic arterial diseases. The fibrinolytic system constitutes a critical response mechanism to intravascular fibrin formation and plays a major role in determining the out come of arterial injury. The overall goal of this application is to define mechanisms that regulate fibrinolysis within the environment of the injured artery. In preliminary studies, we have devised a murine carotid injury model to PAI-1-deficient mice and demonstrated that these animals exhibit enhanced clearance of platelet-rich arterial thrombi. We also hypothesize that binding of plasminogen to arterial thrombi is a major determinant of their clearance, and that factor V and apolipoprotein (a) retard arterial fibrinolysis by inhibiting plasminogen recruitment to sites of arterial injury. To test these hypotheses, we will apply our carotid injury model to transgenic mice that a) lack or overexpress PAI- 1, b) exhibit tissue-specific expression of factor V or express a factor V mutant that is resistant to inactivation by activated protein C, or c) express human apolipoprotein (a). This project has four Specific Aims. Specific Aim 1 is to study the effects of variable and tissue-specific PAI-1 expression on the clearance of acute arterial thrombi in mice. Specific Aim 2 is to determine if apolipoprotein (a) inhibits recruitment of plasminogen to acute arterial thrombi and to determine if platelet factor V contributes to the inhibition of fibrinolysis by platelets. SpecificAim 3 is to examine the time course and cellular characteristics of neointima formation in murine carotid arteries after FeC13 injury and to study the effects of apolipoprotein (a) on neointima formation. Specific Aim 4 is to generate mice transgenic for human plasminogen and to use these animals to probe mechanisms that inhibit the function of exogenous plasminogen activators. The preliminary data outlined in this application as well as the interactive nature of this program project Grant application strongly support the feasibility of these objective. We anticipate that the information gained from these studies will greatly enhance our understanding of mechanisms that regulate fibrin clearance at sites of arterial injury and better define the role of the fibrinolytic system in the pathogenesis of acute and chronic arterial disease.