Published online before print June 26, 2003, doi: 10.1161/01.ATV.0000083297.47245.DA
© 2003 American Heart Association, Inc.
Vascular Biology |
Effect of Hyperhomocystinemia and Hypertension on Endothelial Function in Methylenetetrahydrofolate Reductase–Deficient Mice
From the Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, and Montreal Children’s Hospital Research Institute (R.R.), McGill University, Montreal, Quebec, Canada.
Correspondence to Ernesto L. Schiffrin, MD, PhD, FRCPC, Clinical Research Institute of Montreal, 110 Pine Ave W, Montreal, Quebec, Canada H2W 1R7. E-mail schiffe{at}ircm.qc.ca
Objective— We evaluated the effect of hyperhomocystinemia and angiotensin (Ang) II on vascular function and structure in methylenetetrahydrofolate reductase knockout mice (Mthfr+/-).
Methods and Results— Mthfr+/- and controls (Mthfr+/+) received Ang II (400 ng/kg per min SC) or saline (14 days). Blood pressure, similar in Mthfr+/- and Mthfr+/+, was increased by Ang II. Acetylcholine- and bradykinin-induced relaxations were impaired in mesenteric resistance arteries (pressurized myograph) in Mthfr+/- and in Ang II–infused Mthfr+/+ mice and additionally blunted in Ang II–infused Mthfr+/- mice. The inhibition by L-NAME on acetylcholine was reduced in Mthfr+/- and in Ang II–Mthfr+/+ and absent in Ang II–Mthfr+/- mice. In these groups, vitamin C improved the response to acetylcholine and restored the inhibition by L-NAME. The media to lumen ratio of small arteries, similar in Mthfr+/- and Mthfr+/+, was increased by Ang II. Vascular NADPH oxidase activity, similar in Mthfr+/- and Mthfr+/+, increased after Ang II infusion. Vascular xanthine oxidase activity was also similar in Mthfr+/- and Mthfr+/+. Superoxide production in the aorta was reduced by sepiapterin and by L-NAME, suggesting that reduced bioavailability of tetrahydrobiopterin and uncoupling of nitric oxide synthase were the origin of increased reactive oxygen species in this model.
Conclusions— Mthfr+/- mice show endothelial dysfunction of mesenteric vessels probably attributable to a reduced nitric oxide bioavailability caused by oxidative excess due to uncoupling of nitric oxide synthase without vascular structural alterations. Concurrent Ang II–induced hypertension additionally reduced nitric oxide, increased NADPH oxidase activity, and induced structural alterations. Our findings suggest additive adverse effect of Ang II–dependent hypertension and hyperhomocystinemia on endothelial function.
Key Words: angiotensin • endothelium • free radicals • nitric oxide • small arteries
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