Animal models of atherosclerosis: Overexpression of plasminogen activator inhibitor type 1 (PAI-1) and tissue factor in the rat carotid artery

Prothrombotic and antifibrinolytic genes have been implicated in the pathology and the progression of human atherosclerosis. The atherosclerotic lesion may progress from a fatty streak to a complex plaque which causes morbidity by decreasing lumen diameter and increasing thrombosis. Increased expression of genes thought to promote thrombosis and decrease fibrinolysis have been proposed to create an abnormal thrombotic interface on the atherosclerotic plaque. Two specific gene products, plasminogen activator inhibitor type I (PAI-1) and tissue factor are increased in the atherosclerotic lesion. In normal vessels, PAI-1 is present in the endothelium and media while tissue factor is localized in the adventitia. However, in the intimal lesion, both factors are dramatically increased. They may contribute to local thrombosis and accelerate luminal narrowing by stimulating smooth muscle growth, proliferation and matrix deposition.;Injury of a normal animal artery has been used to gain insights into the progression of fibrous intimal thickening but this injury does not recapitulate all aspects of human lesion progression. Specifically, animal lesions are not chronically thrombogenic, they do not stenose and they do not progress to as great an extent as human lesions. The difference in plaque progression may be due to differences in accumulation of prothrombotic factors such as tissue factor and antifibrinolytic factors such as PAI-1. We have developed a localized transgenic model of gene overexpression that will allow us to test our hypothesis that prothrombotic and antifibrinolytic factors contribute to plaque development. The overall objective of this project is to explore the role of tissue factor and PAI-1in plaque progression and thrombosis utilizing a rat model of arterial injury.;Using this gene overexpression model, we have found that both tissue factor and PAI-1 have a significant impact on several parameters of neointimal formation. PAM expression increases fibrin accumulation, accelerates reendothelialization and decreases neointimal area. Tissue factor increases platelet rich mural thrombus accumulation, accelerates reendothelialization, and increases neointimal area. Taken together, these findings strongly suggest that PAM and tissue factor play important roles in lesion development.