Mutation of Arginine 264 on ERα (Estrogen Receptor Alpha) Selectively Abrogates the Rapid Signaling of Estradiol in the Endothelium Without Altering Fertility
Mutation of Arginine 264 on ERα (Estrogen Receptor Alpha) Selectively Abrogates the Rapid Signaling of Estradiol in the Endothelium Without Altering Fertility
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DOI：
10.1161/atvbaha.120.314159
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发表时间：
2020-09-01
影响因子：
8.7
通讯作者：
Lenfant, Francoise
中科院分区：
文献类型：
--
作者：
Adlanmerini, Marine;Febrissy, Chanaelle;Lenfant, Francoise
目的：ER α（雌激素受体α）发挥核基因组作用，也发挥快速的膜启动类固醇信号传导作用。半胱氨酸451在体内突变为丙氨酸最近揭示了该ER α棕榈酰化位点对17 β-雌二醇（E2）和生育力的一些血管保护作用的关键作用。在这里，我们研究了ER α的精氨酸260的体内作用，其也被描述为参与其E2诱导的PI-3 K（磷酸肌醇3-激酶）以及培养细胞系中G蛋白的快速信号传导。方法和结果：我们产生了一种小鼠模型，该小鼠模型含有该精氨酸的鼠对应物到丙氨酸的点突变（R264 A-ER α）。与C451 A-ER α相反，R264 A-ER α雌性动物具有标准的激素血清水平和正常的下丘脑-垂体卵巢轴控制。虽然R264 A-ER α蛋白丰度正常，但雌二醇的膜ER α依赖性作用，如肠系膜动脉的快速扩张和颈动脉内皮修复的加速，在R264 A-ER α小鼠中被废除。与此形成鲜明对比的是，E2调节的基因表达在子宫和主动脉中高度保留，揭示了完整的核/基因组对E2的反应。一致的是，2个公认的E2的细胞核ER α依赖性作用，即动脉粥样硬化预防和血流介导的动脉重塑被完全保留。结论：这些数据强调了ER α的精氨酸264对E2的内皮膜启动的类固醇信号传导作用的精致作用，但不是对核/基因组作用的精致作用。这提供了第一个无明显内分泌异常的可育小鼠模型，其具有血管功能中快速ER α信号传导的特异性功能丧失。
Objective: ER alpha (estrogen receptor alpha) exerts nuclear genomic actions and also rapid membrane-initiated steroid signaling. The mutation of the cysteine 451 into alanine in vivo has recently revealed the key role of this ER alpha palmitoylation site on some vasculoprotective actions of 17 beta-estradiol (E2) and fertility. Here, we studied the in vivo role of the arginine 260 of ER alpha which has also been described to be involved in its E2-induced rapid signaling with PI-3K (phosphoinositide 3-kinase) as well as G protein in cultured cell lines. Approach and Results: We generated a mouse model harboring a point mutation of the murine counterpart of this arginine into alanine (R264A-ER alpha). In contrast to theC451A-ER alpha, theR264A-ER alpha females are fertile with standard hormonal serum levels and normal control of hypothalamus-pituitary ovarian axis. Although R264A-ER alpha protein abundance was normal, the well-described membrane ER alpha-dependent actions of estradiol, such as the rapid dilation of mesenteric arteries and the acceleration of endothelial repair of carotid, were abrogated inR264A-ER alpha mice. In striking contrast, E2-regulated gene expression was highly preserved in the uterus and the aorta, revealing intact nuclear/genomic actions in response to E2. Consistently, 2 recognized nuclear ER alpha-dependent actions of E2, namely atheroma prevention and flow-mediated arterial remodeling were totally preserved. Conclusions: These data underline the exquisite role of arginine 264 of ER alpha for endothelial membrane-initiated steroid signaling effects of E2 but not for nuclear/genomic actions. This provides the first model of fertile mouse with no overt endocrine abnormalities with specific loss-of-function of rapid ER alpha signaling in vascular functions.