Cerebral vascular dysfunction in methionine synthase-deficient mice

Sanjana DAYAL; Angela M DEVLIN; Ryan B MCCAW; Mei-Lan LIU; Erland ARNING; Teodoro BOTTIGLIERI; Barry SHANE; Frank M FARACI; Steven R LENTZ

doi:10.1161/CIRCULATIONAHA.104.529248

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Cerebral vascular dysfunction in methionine synthase-deficient mice

Journal article

Open access

Peer reviewed

Cerebral vascular dysfunction in methionine synthase-deficient mice

Sanjana DAYAL, Angela M DEVLIN, Ryan B MCCAW, Mei-Lan LIU, Erland ARNING, Teodoro BOTTIGLIERI, Barry SHANE, Frank M FARACI and Steven R LENTZ

Circulation (New York, N.Y.), Vol.112(5), pp.737-744

2005

DOI: 10.1161/CIRCULATIONAHA.104.529248

PMID: 16043641

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Abstract

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 micromol/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 micromol/L, respectively; P<0.001 versus control diet). Dilatation of cerebral arterioles to the endothelium-dependent dilator, acetylcholine (10 micromol/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.

Nervous System

Cardiology. Vascular system

Radiodiagnosis. Nmr imagery. Nmr spectrometry

Investigative techniques, diagnostic techniques (general aspects)

Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous

Atherosclerosis (general aspects, experimental research)

Biological and medical sciences

Medical sciences

Blood and lymphatic vessels

Details

Title: Subtitle: Cerebral vascular dysfunction in methionine synthase-deficient mice
Creators: Sanjana DAYAL - Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, United States
Angela M DEVLIN - Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, United States
Ryan B MCCAW - Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, United States
Mei-Lan LIU - Department of Nutritional Sciences and Toxicology, University of California-Berkeley, United States
Erland ARNING - Baylor Institute of Metabolic Disease, Dallas, Tex, United States
Teodoro BOTTIGLIERI - Baylor Institute of Metabolic Disease, Dallas, Tex, United States
Barry SHANE - Department of Nutritional Sciences and Toxicology, University of California-Berkeley, United States
Frank M FARACI - Department of Pharmacology, University of Iowa, Carver College of Medicine, Iowa City, United States
Steven R LENTZ - Veterans Affairs Medical Center, Iowa City, Iowa, United States
Resource Type: Journal article
Publication Details: Circulation (New York, N.Y.), Vol.112(5), pp.737-744
DOI: 10.1161/CIRCULATIONAHA.104.529248
PMID: 16043641
NLM abbreviation: Circulation
ISSN: 0009-7322
eISSN: 1524-4539
Publisher: Lippincott Williams & Wilkins; Hagerstown, MD
Language: English
Date published: 2005
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040380502771

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