William Harvey Research Institute, Barts and The London Medical School, London, UK.
Br J Pharmacol. 2012 Oct;167(4):805-17. doi: 10.1111/j.1476-5381.2012.02012.x.
Pre-menopausal females have a lower incidence of cardiovascular disease compared with age-matched males, implying differences in the mechanisms and pathways regulating vasoactivity. In small arteries, myogenic tone (constriction in response to raised intraluminal pressure) is a major determinant of vascular resistance. Endothelium-derived dilators, particularly NO, tonically moderate myogenic tone and, because the endothelium is an important target for female sex hormones, we investigated whether NO-mediated moderation of myogenic tone differed between the sexes.
Pressure-diameter or relaxation concentration-response curves to the NO donor spermine-NO or soluble guanylate cyclase (sGC) stimulation (BAY41-2272) were constructed before and following drug intervention in murine mesenteric resistance arteries. Hypotensive responses to activators of the NO-sGC pathway were determined. Quantitative PCR and Western blotting were used for expression analysis.
NO synthase inhibition enhanced myogenic tone of arteries of both sexes while block of endothelium-derived hyperpolarizing factor (EDHF) enhanced responses in arteries of females only. Spermine-NO concentration-dependently relaxed mesenteric arteries isolated from either sex. However, while inhibition of sGC activity attenuated responses of arteries from male mice only, endothelial denudation attenuated responses of arteries from females only. BAY41-2272 and spermine-NO-induced vasodilatation and hypotension were greater in males than in females.
NO moderated myogenic tone in arteries of male mice by a sGC-dependent pathway while EDHF was the predominant endothelial regulator in arteries of females. This is a potentially important sexual dimorphism in NO-mediated reactivity and further implicates EDHF as the predominant endothelial vasodilator in female resistance arteries.
与同龄男性相比，绝经前女性患心血管疾病的发病率较低，这表明调节血管活性的机制和途径存在差异。在小动脉中，肌源性张力（对腔内压力升高的收缩）是血管阻力的主要决定因素。内皮衍生的舒张剂，特别是一氧化氮（NO），在紧张状态下适度调节肌源性张力，由于内皮是女性性激素的重要靶标，因此我们研究了 NO 介导的肌源性张力调节是否存在性别差异。
在药物干预前后，构建了 NO 供体 spermine-NO 或可溶性鸟苷酸环化酶（sGC）刺激（BAY41-2272）的压力-直径或松弛浓度-反应曲线，以测量对 NO-sGC 途径激活剂的降压反应。采用定量 PCR 和 Western blot 进行表达分析。
NO 合酶抑制增强了两性动脉的肌源性张力，而内皮衍生超极化因子（EDHF）的阻断仅增强了雌性动脉的反应。spermine-NO 浓度依赖性地舒张了来自两性的肠系膜动脉。然而，虽然 sGC 活性抑制仅减弱了雄性小鼠动脉的反应，但内皮剥脱仅减弱了雌性小鼠动脉的反应。BAY41-2272 和 spermine-NO 诱导的血管舒张和低血压在雄性中比在雌性中更为明显。
NO 通过 sGC 依赖途径调节雄性小鼠动脉的肌源性张力，而 EDHF 是雌性动脉中主要的内皮调节剂。这是 NO 介导的反应中的一个潜在重要性别二态性，进一步表明 EDHF 是雌性阻力动脉中主要的内皮舒张剂。
