© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Endothelial-dependent vasodilation is reduced in mesenteric arteries from superoxide dismutase knockout mice
Perinatal Research Centre, Departments of Obstetrics/Gynecology and Physiology, 232 HMRC, University of Alberta, Edmonton, Alberta, Canada T6G 2S2
*Corresponding author. Tel.: +1-780-492-1864; fax: +1-780-492-1308. Email address: sandra.davidge{at}ualberta.ca
Objective: Oxidative stress has increasingly been implicated in the development and progression of many vascular diseases. Previous work from our laboratory indicated that peroxynitrite alters vasoactive pathways in endothelial cells, which could potentially reduce vascular relaxation. To test this hypothesis in vivo, we utilized an animal model of endogenous oxidative stress, the CuZn superoxide dismutase (SOD) knockout mouse, to assess vascular function. Methods: Vascular reactivity of mouse mesenteric arteries was assessed in the presence or absence of inhibitors to nitric oxide synthase (NOS) and/or prostaglandin H synthase (PGHS). Endothelial-dependent function was also measured after the addition of exogenous SOD. Peroxynitrite formation was detected by nitrotyrosine immunofluorescence in mesenteric arteries. Results: Our data indicate that endothelial-dependent relaxation responses to methacholine are highly reduced in SOD–/– mice (P<0.01, ANOVA). In only the wild-type mice, NOS or PGHS inhibition significantly blunted relaxation, suggesting that vasodilators from these pathways are present only in the controls and not in SOD–/– mice. A combination of NOS and PGHS inhibitors reduced methacholine relaxation in both wild type and SOD–/– mice. This residual EDHF-like relaxation was not different between groups. After incubation with exogenous SOD, endothelial-dependent relaxation could be partially restored in SOD–/– mice, due to increased NOS-mediated vasodilation. In addition, peroxynitrite formation was significantly elevated in mesenteric arteries from SOD–/– mice. Conclusion: Our data suggest that in a novel animal model of oxidative stress, vessel function is compromised due to alterations in NOS and PGHS-dependent relaxation responses.
KEYWORDS Endothelium; Mesenteric artery; Superoxide dismut; SE knockout mouse; Vascular function; NOS; PGHS
Time for primary review 16 days
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