Sexual dimorphism in obesity-associated endothelial ENaC activity and stiffening in mice.
Sexual dimorphism in obesity-associated endothelial ENaC activity and stiffening in mice.
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DOI：
10.1210/en.2019-00483
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发表时间：
2019-10
期刊：
影响因子：
4.8
通讯作者：
J. Padilla;Makenzie L. Woodford;Guido Lastra-Gonzalez;Vanesa Martinez-Diaz;S. Fujie;Yan Yang;
中科院分区：
文献类型：
--
作者：
J. Padilla;Makenzie L. Woodford;Guido Lastra-Gonzalez;Vanesa Martinez-Diaz;S. Fujie;Yan Yang;
肥胖和胰岛素抵抗使脉管系统变得僵硬，女性似乎受到的不利影响更大。由于动脉僵硬度增加是心血管疾病 (CVD) 的独立预测因素，因此肥胖和胰岛素抵抗女性更容易发生动脉硬化，这可能解释了她们患 CVD 的风险较高。然而，女性更容易遭受与肥胖和胰岛素抵抗相关的动脉硬化的细胞机制仍然很大程度上未知。在这里，我们提供的证据表明，与年龄匹配的雄性小鼠相比，雌性小鼠更容易受到西方饮食引起的内皮细胞硬化的影响。从机制上讲，我们发现西方饮食喂养的雌性小鼠血管内膜硬化的增加伴随着内皮细胞（EnNaC）中上皮钠通道（ENaC）活性的增强。我们的数据进一步表明：1) 与男性相比，通过雌激素受体 α (ERα) 的雌激素信号传导在女性中更大程度地增加 EnNaC 活性，2) 雌激素诱导的 EnNaC 激活是由血清糖皮质激素诱导激酶 1 (SGK-1) 介导的，3) 当缺乏一氧化氮时，雌激素信号传导使内皮细胞变硬，并且这种僵硬效应可以通过以下方法降低：阿米洛利，一种 ENaC 抑制剂。总的来说，我们证明了肥胖相关内皮硬化的性别二态性，即女性比男性更容易受到影响。在女性中，肥胖引起的内皮硬化可能归因于通过 ERα-SGK-1-EnNaC 轴的雌激素信号传导，从而为女性肥胖相关血管硬化建立了假定的治疗靶点。
Obesity and insulin resistance stiffen the vasculature with females appearing to be more adversely affected. As augmented arterial stiffness is an independent predictor of cardiovascular disease (CVD), the increased predisposition of obese and insulin-resistant women to arterial stiffening may explain their heightened risk for CVD. However, the cellular mechanisms by which females are more vulnerable to arterial stiffening associated with obesity and insulin resistance remain largely unknown. Here we provide evidence that female mice are more susceptible to Western diet-induced endothelial cell stiffening compared to age-matched males. Mechanistically, we show that the increased stiffening of the vascular intima in Western diet-fed female mice is accompanied by enhanced epithelial sodium channel (ENaC) activity in endothelial cells (EnNaC). Our data further indicate that: 1) estrogen signaling through estrogen receptor alpha (ERα) increases EnNaC activity to a larger extent in females compared to males, 2) estrogen-induced activation of EnNaC is mediated by the serum glucocorticoid inducible-kinase 1 (SGK-1), and 3) estrogen signaling stiffens endothelial cells when nitric oxide is lacking and this stiffening effect can be reduced with amiloride, an ENaC inhibitor. In aggregate, we demonstrate a sexual dimorphism in obesity-associated endothelial stiffening, whereby females are more vulnerable than males. In females, endothelial stiffening with obesity may be attributed to estrogen signaling through the ERα-SGK-1-EnNaC axis, thus establishing a putative therapeutic target for female obesity-related vascular stiffening.