DESCRIPTION: Plasminogen activator inhibitor - 1 (PAI-1) is the major physiologic inhibitor of tissue and urokinase-type plasminogen activators, which regulate plasmin-mediated proteolysis. PAI-1 accumulation is observed in human atherosclerotic lesions and increased plasma levels of PAI-1 correlate with an increased incidence of myocardial infarction and restenosis. Despite these compelling observations, evidence of a casual role for PAI-1 in cardiovascular disease is circumstantial. In this study, we will test the hypothesis that increased PAI-1 expression directly modifies vascular remodeling after injury. To do this, PAI-1 expression will be specifically increased by transducing balloon-injured rat carotid arteries with an adenovirus expressing rat PAI-1. Preliminary studies have shown that arterial gene transfer of PAI-1 increases neointimal formation. Specific Aim 1: To determine the mechanism by which PAI-1 overexpression increases neointimal formation. The arteries will be assayed for increased fibrin deposition, extracellular matrix synthesis, smooth muscle cell (SMC) proliferation, SMC migration, and/or reduced SMC apoptosis. Specific Aim 2: To determine whether serpin activity, vitronectin binding or both are required for PAI-1 to increase neointimal formation. Mutant PAI-1 molecules that lack serpin or vitronectin binding activity will be expressed in the artery wall and the resultant phenotypes characterized. These studies will define the role of PAI-1 in vascular remodeling. The results may have implications for understanding the pathogenesis of restenosis and atheroma formation.