Published Online
on July 25, 2005

A more recent version of this article appeared on August 2, 2005

This Article Full Text (PDF) All Versions of this Article: 112/5/737    most recent CIRCULATIONAHA.104.529248v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dayal, S. Articles by Lentz, S. R. Search for Related Content PubMed PubMed Citation Articles by Dayal, S. Articles by Lentz, S. R. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Nucleotide Protein UniGene Compound via MeSH Substance via MeSH Related Collections Cerebrovascular disease/stroke Endothelium/vascular type/nitric oxide Animal models of human disease Brain Circulation and Metabolism Genetically altered mice

Submitted on December 12, 2004
Revised on April 28, 2005
Accepted on May 6, 2005

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, and 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.).

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

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.

Key words: cerebrovascular circulation • endothelium • homocysteine • superoxides

This article has been cited by other articles:

				A. M. Devlin, R. Singh, R. E. Wade, S. M. Innis, T. Bottiglieri, and S. R. Lentz Hypermethylation of Fads2 and Altered Hepatic Fatty Acid and Phospholipid Metabolism in Mice with Hyperhomocysteinemia J. Biol. Chem., December 21, 2007; 282(51): 37082 - 37090. [Abstract] [Full Text] [PDF]

				A. Narayanasamy, B. Subramaniam, C. Karunakaran, P. Ranganathan, R. Sivaramakrishnan, T. Sharma, V. S. Badrinath, and J. Roy Hyperhomocysteinemia and Low Methionine Stress Are Risk Factors for Central Retinal Venous Occlusion in an Indian Population Invest. Ophthalmol. Vis. Sci., April 1, 2007; 48(4): 1441 - 1446. [Abstract] [Full Text] [PDF]

				S. M. Colgan and R. C. Austin Homocysteinylation of Metallothionein Impairs Intracellular Redox Homeostasis: The Enemy Within! Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 8 - 11. [Full Text] [PDF]

				S. Dayal, K. M. Wilson, L. Leo, E. Arning, T. Bottiglieri, and S. R. Lentz Enhanced susceptibility to arterial thrombosis in a murine model of hyperhomocysteinemia Blood, October 1, 2006; 108(7): 2237 - 2243. [Abstract] [Full Text] [PDF]

				F. M. Faraci Hydrogen peroxide: watery fuel for change in vascular biology. Arterioscler. Thromb. Vasc. Biol., September 1, 2006; 26(9): 1931 - 1933. [Full Text] [PDF]