Effect of Hyperhomocystinemia and Hypertension on Endothelial Function in Methylenetetrahydrofolate Reductase–Deficient Mice

Author:

Virdis Agostino1,Iglarz Marc1,Neves Mario Fritsch1,Amiri Farhad1,Touyz Rhian M.1,Rozen Rima1,Schiffrin Ernesto L.1

Affiliation:

1. 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.

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

Cited by 70 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3