Virdis Agostino, Iglarz Marc, Neves Mario Fritsch, Amiri Farhad, Touyz Rhian M, Rozen Rima, Schiffrin Ernesto L
Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):1352-7. doi: 10.1161/01.ATV.0000083297.47245.DA. Epub 2003 Jun 26.
We evaluated the effect of hyperhomocystinemia and angiotensin (Ang) II on vascular function and structure in methylenetetrahydrofolate reductase knockout mice (Mthfr+/-).
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.
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.
我们评估了高同型半胱氨酸血症和血管紧张素（Ang）II对亚甲基四氢叶酸还原酶基因敲除小鼠（Mthfr+/-）血管功能和结构的影响。
Mthfr+/-小鼠和对照组（Mthfr+/+）接受Ang II（400 ng/kg每分钟皮下注射）或生理盐水（14天）。Mthfr+/-小鼠和Mthfr+/+小鼠的血压相似，Ang II可使其升高。在Mthfr+/-小鼠以及接受Ang II灌注的Mthfr+/+小鼠的肠系膜阻力动脉（压力肌动描记仪）中，乙酰胆碱和缓激肽诱导的舒张功能受损，而在接受Ang II灌注的Mthfr+/-小鼠中这种受损更为明显。L-NAME对乙酰胆碱的抑制作用在Mthfr+/-小鼠以及接受Ang II处理的Mthfr+/+小鼠中降低，而在接受Ang II处理的Mthfr+/-小鼠中则不存在。在这些组中，维生素C改善了对乙酰胆碱的反应并恢复了L-NAME的抑制作用。小动脉的中膜与管腔比值在Mthfr+/-小鼠和Mthfr+/+小鼠中相似，Ang II可使其升高。血管NADPH氧化酶活性在Mthfr+/-小鼠和Mthfr+/+小鼠中相似，Ang II灌注后升高。血管黄嘌呤氧化酶活性在Mthfr+/-小鼠和Mthfr+/+小鼠中也相似。主动脉中的超氧化物生成可被司来吉兰和L-NAME降低，这表明四氢生物蝶呤的生物利用度降低和一氧化氮合酶的解偶联是该模型中活性氧增加的原因。
Mthfr+/-小鼠表现出肠系膜血管内皮功能障碍，这可能归因于一氧化氮合酶解偶联导致的氧化过量引起的一氧化氮生物利用度降低，且无血管结构改变。同时，Ang II诱导的高血压进一步降低了一氧化氮水平，增加了NADPH氧化酶活性，并诱导了结构改变。我们的研究结果表明，Ang II依赖性高血压和高同型半胱氨酸血症对内皮功能具有累加的不良影响。
