Plasminogen activator inhibitor type I increases neointima formation in balloon-injured rat carotid arteries

Background-Elevated plasma levels of plasminogen activator inhibitor type 1 (PAI-1) are associated with myocardial infarction, atherosclerosis, and restenosis. PAI-1 is increased in atherosclerotic arteries and failed vein grafts. No experimental data, however, support a causal relationship between elevated PAI-1 expression and vascular lesions. Paradoxically, data generated in PAI-1 knockout mice suggest that PAI-1 might decrease lesion formation after arterial injury and that PAM gene transfer might prevent restenosis. Methods and Results-Using the rat carotid balloon injury model and a PAI-1-expressing adenoviral vector, we tested whether elevated arterial PAI-1 expression would alter neointima formation. Compared with control-transduced arteries, neointima formation in PAI-1-transduced arteries was initially retarded. By 14 days, however, the intimas of PAI-1-transduced arteries were significantly larger than intimas of control-transduced arteries (1.6 +/-0.1 X 10(5) versus 1.2 +/-0.1 X 10(5) mum(2), n=18 to 19, P <0.03). PAI-1 expression in individual arteries correlated with increased cell proliferation at 4 and 8 days after injury (R=0.6, P <0.02 and P <0.006). PAM expression also correlated with fibrin(ogen) accumulation (R=0.77, P <0.001), and fibrin(ogen) accumulation correlated strongly with proliferation (R=0.86, P <0.00001). Conclusions-Increased expression of PAI-1 in the artery wall promotes neointima growth after balloon injury. Therefore, despite encouraging data generated in other animal models, PAI-1 is not a promising agent for gene therapy to prevent restenosis. Moreover, our data associate elevated PAI-1 expression with fibrin(ogen) accumulation and increased cell proliferation. These data suggest a mechanism to explain the association between elevated PAI-1 expression and the progression of arterial disease.