Selective deletion of endothelial mineralocorticoid receptor protects from vascular dysfunction in sodium-restricted female mice.
Selective deletion of endothelial mineralocorticoid receptor protects from vascular dysfunction in sodium-restricted female mice.
复制标题
DOI：
10.1186/s13293-020-00340-5
复制
发表时间：
2020-11-23
影响因子：
7.9
通讯作者：
Belin de Chantemèle EJ
中科院分区：
文献类型：
--
作者：
Faulkner JL;Lluch E;Kennard S;Antonova G;Jaffe IZ;Belin de Chantemèle EJ
我们实验室的最新证据表明，女性和雌性小鼠内源性表达比雄性更高的内皮盐皮质激素受体 (ECMR)。越来越多的临床证据还表明，与男性相比，女性在病理状况下醛固酮的产生量更高。然而，在没有合并症的情况下，醛固酮增强 ECMR 激活的作用仍有待探索。目前的研究假设，醛固酮产生增加诱导的 ECMR 激活增加，使健康雌性小鼠容易出现内皮功能障碍。评估饲喂正常盐（NSD，0.4% NaCl）或限钠饮食（SRD，0.05% NaCl）28天的野生型（WT）和ECMR KO（KO）小鼠的主动脉环的血管反应性。 SRD 提高了雌性 WT 小鼠（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) 下，雌性 WT 小鼠的内皮功能（通过对乙酰胆碱的血管舒张评估）较高，而对去氧肾上腺素、血清素和 KCl 的血管收缩性较低。 SRD 损害了雌性（而非雄性）WT 小鼠的内皮功能并增加了血管收缩力，有效消除了基线性别差异。 LNAME 抑制 NOS 后，服用 NSD 的雄性小鼠比雌性小鼠的内皮松弛程度更高，并且消除了 NSD 和 SRD 喂养雌性之间乙酰胆碱松弛反应的差异，表明 NO 在 SRD 介导的内皮功能中发挥作用。与之相关的是，SRD 显着降低了雌性小鼠而非雄性小鼠血管 NOX4 的表达。最后，选择性删除 ECMR 可以保护雌性小鼠免受 SRD 介导的内皮功能障碍和血管收缩力增加的影响。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生醛固酮诱导的内皮功能障碍。此外，这些数据支持 ECMR 在雌性小鼠限钠反应中促进血管收缩的作用。
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.
登录
查看更多内容
影响因子：
8.3
作者：
Faulkner, Jessica L.;Harwood, Daisy;de Chantemele, Eric J. Belin
通讯作者：
de Chantemele, Eric J. Belin
影响因子：
3.2
作者：
Davel AP;Anwar IJ;Jaffe IZ
通讯作者：
Jaffe IZ
影响因子：
37.8
作者：
Huby, Anne-Cecile;Antonova, Galina;de Chantemele, Eric J. Belin
通讯作者：
de Chantemele, Eric J. Belin
醛固酮受体拮抗作用对心肌梗塞后心室重塑和基因表达的性别特异性影响。
DOI：
10.1111/j.1752-8062.2009.00094.x
发表时间：
2009-04
期刊：
Clinical and translational science
影响因子：
--
作者：
Kanashiro-Takeuchi RM;Heidecker B;Lamirault G;Dharamsi JW;Hare JM
通讯作者：
Hare JM
影响因子：
5.6
作者：
Chen, Jing
通讯作者：
Chen, Jing