- Agostino Virdis: Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
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.