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Cerebral Vascular Dysfunction Mediated by Superoxide in Hyperhomocysteinemic Mice

2004; Lippincott Williams & Wilkins; Volume: 35; Issue: 8 Linguagem: Inglês

10.1161/01.str.0000131749.81508.18

1524-4628

Sanjana Dayal, Erland Arning, Teodoro Bottiglieri, Rainer H. Böger, Curt D. Sigmund, Frank M. Faraci, Steven R. Lentz,

Pregnancy and preeclampsia studies

Background and Purpose— Hyperhomocysteinemia is an emerging risk factor for stroke, but little is known about effects of hyperhomocysteinemia on cerebral vascular function. We tested the hypothesis that chronic hyperhomocysteinemia in mice causes endothelial dysfunction in cerebral arterioles through a mechanism that involves superoxide. Methods— Mice heterozygous for a targeted disruption of the cystathionine β-synthase gene ( Cbs +/−) and their wild type littermates ( Cbs +/+) were fed either a control diet or a high-methionine diet for 10 to 12 months. Results— Plasma total homocysteine was elevated with the high-methionine diet compared with the control diet for both Cbs +/+ (7.9±1.0 versus 5.0±0.5 μmol/L; P <0.05) and Cbs +/− (20.5±3.1 versus 8.2±0.9 μmol/L; P <0.001) mice. Dilatation of cerebral arterioles (≈30 μm baseline diameter) was measured in vivo in response to the endothelium-dependent dilator acetylcholine or the endothelium-independent dilator nitroprusside. Vasodilatation to acetylcholine was impaired with the high-methionine diet compared with the control diet for both Cbs +/+ and Cbs +/− mice ( P <0.01). Dilatation of arterioles to acetylcholine was restored toward normal by the superoxide scavenger tiron ( P <0.05). Vasodilatation to nitroprusside was not influenced by Cbs genotype or diet. Dihydroethidium (DHE) staining for vascular superoxide was elevated in Cbs +/− mice fed the high-methionine diet and was inhibited by apocynin or Nω-nitro- l -arginine methyl ester, implicating NAD(P)H oxidase and nitric oxide synthase as potential sources of superoxide. Conclusions— Superoxide is a key mediator of endothelial dysfunction in the cerebral circulation during diet-induced hyperhomocysteinemia.