Tissue Factor Overexpression in Rat Arterial Neointima Models Thrombosis and Progression of Advanced Atherosclerosis

Abstract

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.