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(Circulation. 2005;112:737-744.)
© 2005 American Heart Association, Inc.

Stroke

Cerebral Vascular Dysfunction in Methionine Synthase–Deficient Mice

Sanjana Dayal, PhD; Angela M. Devlin, PhD; Ryan B. McCaw, BS; Mei-Lan Liu, PhD; Erland Arning, PhD; Teodoro Bottiglieri, PhD; Barry Shane, PhD; Frank M. Faraci, PhD; Steven R. Lentz, MD, PhD

From the Departments of Internal Medicine (S.D., A.M.D., R.B.M., F.M.F., S.R.L.) and Pharmacology (F.M.F.), University of Iowa, Carver College of Medicine, Iowa City; Baylor Institute of Metabolic Disease, Dallas, Tex (E.A., T.B.); Department of Nutritional Sciences and Toxicology, University of California–Berkeley (M.-L.L., B.S.); and Veterans Affairs Medical Center, Iowa City, Iowa (S.R.L.).

Correspondence to Steven R. Lentz, MD, PhD, Department of Internal Medicine, C32 GH, University of Iowa, Iowa City, IA 52242. E-mail steven-lentz{at}uiowa.edu

Received December 12, 2004; revision received April 28, 2005; accepted May 6, 2005.

Background— Methionine synthase (MS) catalyzes the folate-dependent remethylation of homocysteine to methionine. We tested the hypothesis that deficiency of MS impairs endothelial function in mice heterozygous for disruption of the Mtr gene, which encodes MS.

Methods and Results— Plasma total homocysteine was similar in wild-type (Mtr^+/+) and heterozygous (Mtr^+/–) mice fed a control diet (4.5±0.3 and 5.3±0.4 µmol/L, respectively) and mildly elevated in Mtr^+/+ and Mtr^+/– mice fed a low-folate (LF) diet (7.5±0.7 and 9.6±1.2 µmol/L, respectively; P<0.001 versus control diet). Dilatation of cerebral arterioles to the endothelium-dependent dilator, acetylcholine (10 µmol/L) was blunted in Mtr^+/– mice compared with Mtr^+/+ mice fed the control diet (21±4 versus 32±4%; P<0.05). Both Mtr^+/+ and Mtr^+/– mice exhibited impaired dilatation of cerebral arterioles to acetylcholine when they were fed the LF diet (12±2 and 14±2%, respectively; P<0.01 versus Mtr^+/+ mice fed the control diet). Elevated levels of superoxide and hydrogen peroxide were detected by confocal microscopy in cerebral arterioles of Mtr^+/– mice fed the control diet and in both Mtr^+/+ and Mtr^+/– mice fed the LF diet.

Conclusions— These findings demonstrate that defective homocysteine remethylation caused by deficiency of either MS or folate produces oxidative stress and endothelial dysfunction in the cerebral microcirculation of mice.

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