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 dise ase. It might also affect intimal area by increasing matrix accumulation an d stimulating smooth muscle cell (SMC) migration and proliferation. To test this hypothesis, we overexpressed tissue factor in a rat model of the huma n fibrous plaque. Methods and Results-A neointima was generated by seeding tissue factor-over expressing rat SMCs onto the luminal surface of a balloon-injured syngeneic rat carotid artery. The cells attached and expressed tissue factor over th e long term. Mural thrombus accumulation was present at 4 and 7 days and in creased neointimal SMC numbers and area by 2-fold at 2 and 4 weeks. Tissue factor overexpression accelerated reendothelialization compared with contro ls at 2 weeks and 1 month. Tissue factor-overexpressing SMCs exhibited incr eased migration both in vitro and in vivo. The increased migration by tissu e factor-overexpressing SMCs in vitro was not dependent on activation of th e 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.