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on June 3, 2004

A more recent version of this article appeared on August 1, 2004

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Submitted on February 12, 2003
Revised on March 31, 2004
Accepted on April 20, 2004

Cerebral Vascular Dysfunction Mediated by Superoxide in Hyperhomocysteinemic Mice

Sanjana Dayal PhD; Erland Arning PhD; Teodoro Bottiglieri PhD; Rainer H. Böger MD; Curt D. Sigmund PhD; Frank M. Faraci PhD; and Steven R. Lentz MD, PhD^*

From the Departments of Internal Medicine (S.D., C.D.S., F.M.F., S.R.L.), Physiology and Biophysics (C.D.S.), and Pharmacology (F.M.F.), University of Iowa Carver College of Medicine, Iowa City, Iowa; Baylor Institute of Metabolic Disease (E.A., T.B.), Dallas, Texas; the Institute of Experimental and Clinical Pharmacology and Toxicology (R.H.B.), University Hospital Hamburg-Eppendorf, Hamburg, Germany; and Veterans Affairs Medical Center (S.R.L.), Iowa City, Iowa.

^* To whom correspondence should be addressed. E-mail: steven-lentz{at}uiowa.edu.

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 -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 N-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.

Key words: cerebral • endothelium • homocysteine • stroke • superoxides

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