Recent evidence by our laboratory demonstrates that women and female mice endogenously express higher endothelial mineralocorticoid receptor (ECMR) than males. Mounting clinical evidence also indicates that aldosterone production is higher in pathological conditions in females compared to males. However, the role for increased activation of ECMR by aldosterone in the absence of a comorbid condition is yet to be explored. The current study hypothesized that increased ECMR activation induced by elevated aldosterone production predisposes healthy female mice to endothelial dysfunction. Vascular reactivity was assessed in aortic rings from wild-type (WT) and ECMR KO (KO) mice fed either a normal salt (NSD, 0.4% NaCl) or sodium-restricted diet (SRD, 0.05% NaCl) for 28 days. SRD elevated plasma aldosterone levels as well as adrenal CYP11B2 and angiotensin II type 1 receptor (AT1R) expressions in female, but not male, WT mice. In baseline conditions (NSD), endothelial function, assessed by vascular relaxation to acetylcholine, was higher while vascular contractility to phenylephrine, serotonin, and KCl lower in female than male WT mice. SRD impaired endothelial function and increased vascular contractility in female, but not male, WT mice effectively ablating the baseline sex differences. NOS inhibition with LNAME ablated endothelial relaxation to a higher extent in male than female mice on NSD and ablated differences in acetylcholine relaxation responses between NSD- and SRD-fed females, indicating a role for NO in SRD-mediated endothelial function. In association, SRD significantly reduced vascular NOX4 expression in female, but not male, mice. Lastly, selective deletion of ECMR protected female mice from SRD-mediated endothelial dysfunction and increased vascular contractility. Collectively, these data indicate that female mice develop aldosterone-induced endothelial dysfunction via endothelial MR-mediated reductions in NO bioavailability. In addition, these data support a role for ECMR to promote vascular contractility in female mice in response to sodium restriction.

中文翻译：

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选择性缺失内皮盐皮质激素受体可保护钠限制雌性小鼠免受血管功能障碍

我们实验室的最新证据表明，女性和雌性小鼠内源性表达的内皮盐皮质激素受体 (ECMR) 高于雄性。越来越多的临床证据还表明，与男性相比，女性在病理条件下醛固酮的产生更高。然而，在没有合并症的情况下，醛固酮增加 ECMR 激活的作用仍有待探索。目前的研究假设，醛固酮生成升高诱导的 ECMR 激活增加会使健康雌性小鼠易患内皮功能障碍。在饲喂正常盐（NSD，0.4% NaCl）或限钠饮食（SRD，0.05% NaCl）28 天的野生型 (WT) 和 ECMR KO (KO) 小鼠的主动脉环中评估血管反应性。SRD 提高了雌性（而非雄性）WT 小鼠的血浆醛固酮水平以及肾上腺 CYP11B2 和血管紧张素 II 1 型受体 (AT1R) 的表达。在基线条件 (NSD) 中，通过血管舒张对乙酰胆碱评估的内皮功能较高，而女性对去氧肾上腺素、血清素和 KCl 的血管收缩性低于雄性 WT 小鼠。SRD 在雌性而非雄性 WT 小鼠中损害内皮功能并增加血管收缩性，从而有效地消除基线性别差异。LNAME 抑制 NOS 在雄性小鼠中比 NSD 雌性小鼠的内皮松弛程度更高，并且在 NSD 和 SRD 喂养的雌性之间消除乙酰胆碱松弛反应的差异，表明 NO 在 SRD 介导的内皮功能中的作用。关联，SRD 显着降低了雌性小鼠而非雄性小鼠的血管 NOX4 表达。最后，选择性删除 ECMR 保护雌性小鼠免受 SRD 介导的内皮功能障碍和血管收缩性增加。总的来说，这些数据表明雌性小鼠通过内皮 MR 介导的 NO 生物利用度降低而发展为醛固酮诱导的内皮功能障碍。此外，这些数据支持 ECMR 促进雌性小鼠对钠限制作出反应的血管收缩性的作用。