Enhanced tissue factor (TF) expression within atherosclerotic lesions is considered a critical determinant of arterial thrombosis. However, tissue factor expression is not restricted to the blood vessel wall, and recent studies suggest that circulating leukocytes contain a pool of TF that can be mobilized rapidly to support platelet-dependent arterial thrombosis. The overall goals of this application are to define the roles of circulating tissue factor in acute arterial thrombosis and normal hemostasis, and to elucidate how leukocyte expression of tissue factor contributes to atherosclerosis progression and plaque thrombogenicity. We have developed a murine model of carotid artery injury that generates platelet-rich thrombi in a tissue factor dependent manner. We have shown that this model can identify molecular determinants of thrombosis and thrombolysis in injured arteries, and we have utilized hematopoietic stem cell transplant strategies to restrict gene expression in mice. We have documented that active TF is present in mouse peripheral blood, and that TF antigen is present in murine atherosclerotic lesions. In the proposed experiments we will test the following hypotheses: 1) circulating TF is an important determinant of platelet thrombosis and normal hemostasis after vascular injury, 2) leukocyte-derived TF plays a key role in atherosclerosis development in mice, and 3) thrombosis in atherosclerotic arteries depends not only on vascular wall TF, but also on blood-associated TF, the levels of which are responsive to circulating lipid concentrations. In collaboration Drs. Owen and Simari Mayo Clinic, we will test these hypotheses in a series of in vivo experiments that apply our thrombosis models to mice whose tissue factor expression is restricted by gene targeting and hematopoietic stem cell transplant strategies. The proposed experiments will test in vivo a hypothesis that challenges a central paradigm in arterial thrombosis-that thrombogenic TF originates solely from the vascular wall. We anticipate that our studies will: 1) elucidate new mechanisms by which leukocytes and tissue factor regulate platelet-dependent thrombosis, and 2) provide important insights into the role of leukocyte TF in atherosclerosis development and plaque thrombogenicity. These experiments have important implications for fur understanding, treatment, and prevention of arterial thrombosis and atherosclerosis.
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