Recent findings from our group demonstrated that females exhibit higher endothelial mineralocorticoid receptor (MR) expression than males which predisposes them to aldosterone-mediated endothelial dysfunction in the context of metabolic disorders. However, whether the endothelium of female mice presents a higher propensity to MR-mediated dysfunction than that of males in the absence of comorbidities remains unknown. We therefore sought to investigate whether increasing aldosterone production endogenously with sodium restriction impairs endothelial function in otherwise healthy female mice. We fed male and female Balb/C mice a normal (0.4% NaCl, NSD) or sodium restricted diet (0.05% NaCl, SRD) for 4 weeks. Females exhibited higher baseline endothelial function (relaxation to acetylcholine) and lower vascular contractility (constriction to phenylephrine, serotonin and KCl). However, SRD impaired endothelial-dependent relaxation and increased vascular contractility in female mice, effectively ablating the baseline sex-difference. Female sex also increased baseline adrenal CYP11B2 expression, however, SRD significantly enhanced CYP11B2 expression in male and female mice and ablated the sex difference. NOS inhibition with LNAME eliminated both sex as well as diet-induced differences in endothelial dysfunction. In accordance, females demonstrated higher vascular eNOS expression at baseline, which SRD significantly decreased. In addition, SRD diminished vascular NOX4 expression in female mice only. MR blockade with spironolactone protected female mice from decreases in endothelial-dependent relaxation, but not increases in vascular contractility. Utilizing sodium restriction as a method to increase plasma aldosterone levels in healthy female mice we demonstrated that female mice are more susceptible to vascular damage via MR-activation in the vascular endothelium only.

中文翻译：

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饮食钠限制通过盐皮质激素受体依赖性降低 Balb/C 小鼠的 NO 生物利用度而损害内皮功能


我们小组的最新研究结果表明，女性比男性表现出更高的内皮盐皮质激素受体（MR）表达，这使得她们在代谢紊乱的情况下容易出现醛固酮介导的内皮功能障碍。然而，在没有合并症的情况下，雌性小鼠的内皮细胞是否比雄性小鼠更容易出现 MR 介导的功能障碍，目前尚不清楚。因此，我们试图研究通过限钠来增加内源性醛固酮的产生是否会损害健康雌性小鼠的内皮功能。我们给雄性和雌性 Balb/C 小鼠喂食正常（0.4% NaCl，NSD）或钠限制饮食（0.05% NaCl，SRD）4周。女性表现出较高的基线内皮功能（对乙酰胆碱的松弛）和较低的血管收缩性（对去氧肾上腺素、血清素和氯化钾的收缩）。然而，SRD 损害了雌性小鼠的内皮依赖性舒张并增加了血管收缩力，有效消除了基线性别差异。雌性也增加了基线肾上腺 CYP11B2 表达，然而，SRD 显着增强了雄性和雌性小鼠的 CYP11B2 表达，并消除了性别差异。 LNAME 抑制 NOS 消除了性别和饮食引起的内皮功能障碍差异。与此一致的是，女性在基线时表现出较高的血管 eNOS 表达，而 SRD 显着降低。此外，SRD 仅减少雌性小鼠血管 NOX4 的表达。用螺内酯阻断 MR 可以保护雌性小鼠免受内皮依赖性舒张的减少，但不会增加血管收缩性。 利用钠限制作为增加健康雌性小鼠血浆醛固酮水平的方法，我们证明雌性小鼠更容易通过仅血管内皮中的 MR 激活而受到血管损伤。