Role of GPER in estrogen-dependent nitric oxide formation and vasodilation.
Role of GPER in estrogen-dependent nitric oxide formation and vasodilation.
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DOI：
10.1016/j.jsbmb.2017.05.006
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Prossnitz ER
中科院分区：
文献类型：
--
作者：
Fredette NC;Meyer MR;Prossnitz ER
雌激素是血管张力的有效调节剂，但潜在的受体和配体特异性信号通路仍然缺乏特征。主要生理性雌激素17β-雌二醇（E2）是经典核雌激素受体（ERα和ERβ）以及G蛋白偶联雌激素受体（GPER）的非选择性激动剂，其刺激内皮细胞中血管扩张剂一氧化氮（NO）的形成。在这里，我们研究了GPER信号在E2依赖性激活内皮NO形成和随后的血管舒张中的作用。使用E2和GPER选择性激动剂G-1，我们研究了人内皮细胞中eNOS磷酸化和NO形成，以及野生型和GPER缺陷小鼠动脉中内皮依赖性血管舒张。E2和G-1诱导eNOS在激活位点Ser 1177的磷酸化程度相似。内皮细胞NO生产E2是可比的G-1，并大大减少后，药理学抑制GPER。类似地，临床上使用的ER靶向药物4 OH-他莫昔芬、雷洛昔芬和ICI 182，780（法仕得，氟维司群™）部分地通过GPER诱导NO形成。我们确定c-Src，EGFR，PI 3 K和ERK信号通路参与GPER依赖的NO形成。与细胞中NO形成的激活一致，E2和G-1在野生型小鼠的主动脉中诱导同样有效的血管舒张。Gper缺失完全消除了对G-1的血管舒张反应，同时降低了对E2的反应约50%。这些结果表明，相当大一部分E2诱导的内皮依赖性血管舒张和NO的形成是由GPER介导的。因此，选择性靶向血管GPER可能是激活内皮NO通路的合适方法，可能导致血管张力降低和抑制动脉粥样硬化性血管疾病。
Estrogens are potent regulators of vascular tone, yet underlying receptor- and ligand-specific signaling pathways remain poorly characterized. The primary physiological estrogen 17β-estradiol (E2), a non-selective agonist of classical nuclear estrogen receptors (ERα and ERβ) as well as the G protein-coupled estrogen receptor (GPER), stimulates formation of the vasodilator nitric oxide (NO) in endothelial cells. Here, we studied the contribution of GPER signaling in E2-dependent activation of endothelial NO formation and subsequent vasodilation. Employing E2 and the GPER-selective agonist G-1, we investigated eNOS phosphorylation and NO formation in human endothelial cells, and endothelium-dependent vasodilation in the aortae of wild-type and Gper-deficient mice. Both E2 and G-1 induced phosphorylation of eNOS at the activation site Ser1177 to similar extents. Endothelial NO production to E2 was comparable to that of G-1, and was substantially reduced after pharmacological inhibition of GPER. Similarly, the clinically used ER-targeting drugs 4OH-tamoxifen, raloxifene, and ICI182,780 (faslodex, fulvestrant™) induced NO formation in part via GPER. We identified c-Src, EGFR, PI3K and ERK signaling pathways to be involved in GPER-dependent NO formation. In line with activation of NO formation in cells, E2 and G-1 induced equally potent vasodilation in the aorta of wild-type mice. Gper deletion completely abrogated the vasodilator response to G-1, while reducing the response to E2 by ~50%. These findings indicate that a substantial portion of E2-induced endothelium-dependent vasodilation and NO formation is mediated by GPER. Thus, selective targeting of vascular GPER may be a suitable approach to activate the endothelial NO pathway, possibly leading to reduced vascular tone and inhibition of atherosclerotic vascular disease.
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影响因子：
4.8
作者：
Boo, YC;Sorescu, G;Jo, HJ
通讯作者：
Jo, HJ
DOI：
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发表时间：
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期刊：
Trends in endocrinology and metabolism: TEM
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