Cerebral vascular dysfunction in methionine synthase-deficient mice.
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.


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.
Dayal
Sanjana
S
Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, USA.
Devlin
Angela M
AM
McCaw
Ryan B
RB
Liu
Mei-Lan
ML
Arning
Erland
E
Bottiglieri
Teodoro
T
Shane
Barry
B
Faraci
Frank M
FM
Lentz
Steven R
SR
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002561:Cerebrovascular Disorders / Q000201:enzymology / Q000235:genetics*; D006580:Genetic Carrier Screening; D006710:Homocysteine / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D014664:Vasodilation / Q000187:drug effects
D006710:Homocysteine; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase