Potential roles of plasminogen activator system in coronary vascular remodeling induced by long-term nitric oxide synthase inhibition

Koichi Kaikita, John A. Schoenhard, Corrie A. Painter, Robert T. Ripley, Nancy J. Brown, Agnes B. Fogo, Douglas E. Vaughan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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 with Nω-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±3 mmHg (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.

Original languageEnglish (US)
Pages (from-to)617-627
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Issue number6
StatePublished - Jun 1 2002


  • Collagen
  • Hypertension
  • Nitric oxide synthase
  • Plasminogen activators
  • Vascular fibrosis

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine


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