K. Kaikita, J. A. Schoenhard, C. A. Painter, R. T. Ripley, N. J. Brown, A. B. Fogo and D. E. Vaughan. Potential Roles of Plasminogen Activator System in Coronary Vascular Remodeling Induced by Long-term Nitric Oxide Synthase Inhibition. Journal of Molecular and Cellular Cardiology (2002) 34, 617–627. Recent studies have indicated that a number of factors contribute to the pathophysiology in response to nitric oxide synthase (NOS) inhibition. We previously demonstrated that plasminogen activator inhibitor-1 deficient (PAI-1^−/−) mice are protected against hypertension and perivascular fibrosis induced by relatively short-term NOS inhibition. In this study, we compared the temporal changes in systolic blood pressure and coronary perivascular fibrosis induced by long-term treatment withN^ω -nitro- L -arginine methyl ester (L -NAME) in wild type (WT), PAI-1^−/− and tissue-type plasminogen activator deficient (t-PA^−/−) mice. After initiating L -NAME, systolic blood pressure increased in all groups at 2 weeks. Over a 16 week study period, systolic blood pressure increased to 143±3mmHg (mean±SEM) in WT animals, 139±2 in t-PA^−/− mice vs 129±2 in PAI-1^−/− mice (P < 0.01). Coronary perivascular fibrosis increased in L -NAME-treated WT and t-PA^−/− mice compared to each control group (P<0.01 in WT, P<0.05 in t-PA^−/−), while PAI-1^−/− mice were protected against fibrosis induced by L -NAME. t-PA deficiency did not accentuate the vascular pathology or the changes in blood pressure. In situ zymography demonstrated augmented gelatinolytic activity in PAI-1^−/− mice at baseline, suggesting that PAI-1 deficiency prevents the increase of collagen deposition by promoting matrix degradation. Plasma TGF-β1 levels increased in L -NAME-treated WT and PAI-1^−/− mice (P < 0.01), but not in L -NAME-treated t-PA^−/− mice. These findings support the hypothesis that the plasminogen activator system protects against the structural vascular changes induced by long-term NOS inhibition. While PAI-1 deficiency protects against L -NAME-induced hypertension and perivascular fibrosis, t-PA deficiency does not exacerbate the vascular pathology or hypertension.