Tissue factor overexpression in rat arterial neointima models thrombosis and progression of advanced atherosclerosis

Background-Tissue factor located in the atherosclerotic plaque might cause the clinically significant thrombotic events associated with end-stage disease. It might also affect intimal area by increasing matrix accumulation and stimulating smooth muscle cell (SMC) migration and proliferation. To test this hypothesis, we overexpressed tissue factor in a rat model of the human fibrous plaque. Methods and Results-A neointima was generated by seeding tissue factor-overexpressing rat SMCs onto the luminal surface of a balloon-injured syngeneic rat carotid artery. The cells attached and expressed tissue factor over the long term. Mural thrombus accumulation was present at 4 and 7 days and increased neointimal SMC numbers and area by 2-fold at 2 and 4 weeks. Tissue factor overexpression accelerated reendothelialization compared with controls at 2 weeks and 1 month. Tissue factor-overexpressing SMCs exhibited increased migration both in vitro and in vivo. The increased migration by tissue factor-overexpressing SMCs in vitro was not dependent on activation of the coagulation cascade and could be blocked by an inhibitor of tissue factor. Conclusions-These results suggest that tissue factor plays a direct role in neointimal development by coagulation-dependent and -independent pathways.