title: Effect of hyperhomocystinemia and hypertension on endothelial function in methylenetetrahydrofolate reductase-deficient mice.
abstract: OBJECTIVE
  We evaluated the effect of hyperhomocystinemia and angiotensin (Ang) II on vascular function and structure in methylenetetrahydrofolate reductase knockout mice (Mthfr+/-).
  
  
  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.
authors.affiliation: Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Agostino
authors.initials: A
authors.lastname: Virdis
authors.forename: Marc
authors.initials: M
authors.lastname: Iglarz
authors.forename: Mario Fritsch
authors.initials: MF
authors.lastname: Neves
authors.forename: Farhad
authors.initials: F
authors.lastname: Amiri
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.forename: Rima
authors.initials: R
authors.lastname: Rozen
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001682:Biological Availability; D004730:Endothelium, Vascular / Q000378:metabolism*; D020138:Hyperhomocysteinemia / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology*; D066298:In Vitro Techniques; D008638:Mesenteric Arteries / Q000378:metabolism; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D013481:Superoxides; D000804:Angiotensin II; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D014969:Xanthine Oxidase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D019255:NADPH Oxidases; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester