Vascular Biology Center, Medical College of Georgia at Augusta University, 1460 Laney Walker Blvd, Augusta, GA, 30912, USA.
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, USA.
Biol Sex Differ. 2020 Nov 23;11(1):64. doi: 10.1186/s13293-020-00340-5.
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.
我们实验室的最新研究表明，女性和雌性小鼠内源性表达的内皮矿物ocorticoid 受体（ECMR）高于男性。越来越多的临床证据也表明，与男性相比，女性在病理条件下的醛固酮生成更高。然而，在没有合并症的情况下，醛固酮对 ECMR 的激活增加的作用仍有待探索。本研究假设，醛固酮产生增加导致的 ECMR 激活使健康雌性小鼠易发生内皮功能障碍。
在给予正常盐（NSD，0.4%NaCl）或低盐（SRD，0.05%NaCl）饮食 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 升高了雌性而非雄性 WT 小鼠的血浆醛固酮水平以及肾上腺 CYP11B2 和血管紧张素 II 型 1 受体（AT1R）的表达。在基础条件（NSD）下，雌性 WT 小鼠的血管舒张反应（乙酰胆碱）更高，而对苯肾上腺素、血清素和 KCl 的血管收缩反应更低。SRD 损害了雌性 WT 小鼠的内皮功能并增加了血管收缩性，有效地消除了基础状态下的性别差异。NOS 抑制（LNAME）在 NSD 喂养的雄性而非雌性小鼠中对内皮舒张的抑制作用更大，并消除了 NSD 和 SRD 喂养雌性之间乙酰胆碱舒张反应的差异，表明 NO 在 SRD 介导的内皮功能中起作用。相应地，SRD 显著降低了雌性而非雄性小鼠的血管 NOX4 表达。最后，ECMR 的选择性缺失保护了雌性小鼠免受 SRD 介导的内皮功能障碍和增加的血管收缩性。
总之，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，发展出醛固酮诱导的内皮功能障碍。此外，这些数据支持 ECMR 在女性对钠限制的反应中促进血管收缩的作用。
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