Endothelial-dependent vasodilation is reduced in mesenteric arteries from superoxide dismutase knockout mice.
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.


CONCLUSIONS
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.
Cooke
Christy Lynn M
CL
Perinatal Research Centre, Department of Obstetrics/Gynecology, 232 HMRC, University of Alberta, T6G 2S2 Edmonton, Alberta, Canada.
Davidge
Sandra T
ST
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008469:Meclofenamic Acid / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000502:physiology*; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000235:genetics* / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D002121:Calcium Channel Blockers; D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; D016210:Methacholine Chloride; D018999:Charybdotoxin; D009599:Nitroprusside; D001030:Apamin; D008469:Meclofenamic Acid; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D019331:NG-Nitroarginine Methyl Ester