title: Potential roles of plasminogen activator system in coronary vascular remodeling induced by long-term nitric oxide synthase inhibition.
abstract: 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 N(omega)-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-beta1 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.
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kaikita
authors.forename: John A
authors.initials: JA
authors.lastname: Schoenhard
authors.forename: Corrie A
authors.initials: CA
authors.lastname: Painter
authors.forename: Robert T
authors.initials: RT
authors.lastname: Ripley
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vaughan
mesh_terms: D000818:Animals; D001835:Body Weight; D003327:Coronary Disease / Q000209:etiology / Q000517:prevention & control; D003331:Coronary Vessels / Q000473:pathology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D006439:Hemodynamics; D006973:Hypertension / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D010960:Plasminogen Activators / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000097:blood
chemical_list: D004791:Enzyme Inhibitors; D016212:Transforming Growth Factor beta; D019001:Nitric Oxide Synthase; D010960:Plasminogen Activators; D019331:NG-Nitroarginine Methyl Ester