title: Increased superoxide leads to decreased flow-induced dilation in resistance arteries of Mn-SOD-deficient mice.
abstract: The role of mitochondrial manganese-superoxide dismutase (Mn-SOD) in the maintenance of vascular function has not yet been studied. Thus we examined flow- and agonist-induced dilations in isolated mesenteric arteries (approximately 90 microm in diameter) of Mn-SOD heterozygous (Mn-SOD+/-) and wild-type (WT) mice. Increases in flow elicited dilations in all vessels, but the magnitude of the dilation was significantly less in vessels of Mn-SOD+/- mice than in those of WT mice (64 vs. 74% of passive diameter). N(omega)-nitro-L-arginine methyl ester inhibited the dilation in vessels of WT mice but had no effect on vessels of Mn-SOD+/- mice. Tempol or tiron (superoxide scavengers) increased flow-induced dilation in vessels of Mn-SOD+/- mice. Acetylcholine- and sodium nitroprusside-induced, but not adenosine-induced, dilations were also decreased in arteries of Mn-SOD+/- mice. Superoxide levels in the arteries of Mn-SOD+/- mice were significantly increased. Western blot analysis confirmed a 50% reduction of Mn-SOD protein in the vessels of Mn-SOD+/- mice. A 41% reduction in endothelial nitric oxide synthase (eNOS) protein and a 37% reduction in eNOS activity were also found in the vessels of Mn-SOD+/- mice. Whereas there was no difference in eNOS protein in kidney homogenates of WT and Mn-SOD+/- mice, a significant reduction of nitric oxide synthase activity was found in Mn-SOD+/- mice, which could be restored by the administration of tiron. We conclude that an increased concentration of superoxide due to reduced activity of Mn-SOD, which inactivates nitric oxide and inhibits eNOS activity, contributes to the impaired vasodilator function of isolated mesenteric arteries of Mn-SOD+/- mice. These results suggest that Mn-SOD contributes significantly to the regulation of vascular function.
authors.affiliation: Deptartment of Physiology, New York Medical College, Valhalla, New York 10595, USA.
authors.forename: Changdong
authors.initials: C
authors.lastname: Yan
authors.forename: An
authors.initials: A
authors.lastname: Huang
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wu
authors.forename: Pawel M
authors.initials: PM
authors.lastname: Kaminski
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolin
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hintze
authors.forename: Gabor
authors.initials: G
authors.lastname: Kaley
authors.forename: Dong
authors.initials: D
authors.lastname: Sun
mesh_terms: D000818:Animals; D004730:Endothelium, Vascular / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D008297:Male; D008638:Mesenteric Arteries / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D012039:Regional Blood Flow / Q000502:physiology; D013314:Stress, Mechanical; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D014665:Vasodilator Agents; D013481:Superoxides; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D013482:Superoxide Dismutase