Arterial thrombosis, a major complication of atherosclerosis, is the leading cause of death in the Western world. Thrombosis in vivo is usually initiated when endoluminal disruption leads to exposure of subendothelial procoagulants such as tissue factor (TF) to flowing blood, with binding of TF to factor VIIa resulting in activation of factors IX and X and subsequent fibrin deposition. Tissue factor pathway inhibitor (TFPI), a Kunitz-type serine-protease inhibitor, uniquely modifies the coagulation cascade in vivo by binding in a two-step process to TF-factor VIIa catalytic complex and factor Xa forming a quaternary inhibitory complex which dampens further coagulation. We have recently demonstrated that in spite of TFPI expression in atherosclerotic plaque, TF activity predominates. Thus our working hypothesis is that there is a relative deficiency of TFPI in atherosclerotic plaque and that the imbalance between TF and TFPI is an important source of vascular thrombogenicity and may contribute to plaque development and progression. To further define the importance of this imbalance, we propose two major goals. First, we will generate genetically modified mice that overexpress TFPI in a targeted manner limited to the vessel wall to determine whether altering the local balance favoring TF inhibition will inhibit arterial thrombosis and the development and progression of atherosclerosis. Second, to alter this balance in blood- derived cells, we will generate mice incapable of producing TFPI from circulating blood cells and test these mice in an established model of thrombosis.
Our Specific Aims are: 1) To generate transgenic mice which overexpress TFPI in a targeted manner, 2) To determine the role of vascular TFPI overexpression in the development of atherosclerosis, 3) To determine the role of vascular TFPI expression in a murine model of arterial thrombosis and 4) To determine the role of blood-derived TFPI expression in a murine model of arterial thrombosis. We anticipate that these studies will; 1) elucidate new mechanisms by which the balance between TF and TFPI regulates the development of atherosclerosis and thrombosis and 2) provide insights into the relative importance of blood-derived and circulating forms of TFPI. Ultimately these insights will lead to new therapeutic approaches to prevent and treat atherosclerosis and its most important complication, thrombosis.
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