Vascular cell signaling by membrane estrogen receptors
Vascular cell signaling by membrane estrogen receptors
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DOI：
10.1016/j.steroids.2005.02.011
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发表时间：
2005-05-01
期刊：
影响因子：
2.7
通讯作者：
Bender, JR
中科院分区：
文献类型：
--
作者：
Hisamoto, K;Bender, JR
由于绝经前女性与同龄男性在临床上明显的冠心病（CHD）发病率方面存在显著的性别差异，因此对雌激素对血管壁的影响有很大的兴趣。最近的随机临床试验意外地未能证明激素替代疗法（HRT）对绝经后妇女冠心病二级或一级预防的益处。对于这些发现有几种可能的解释，鉴于雌激素在细胞、分子甚至动物模型水平上显示的许多潜在的有益血管作用，这些发现创造了一个难题。临床试验正在进行中，分子途径的解剖也在继续。虽然雌激素受体（er）传统上被定义为配体激活的转录激活因子或抑制因子，这一现象肯定与雌激素对血管细胞的一些有益作用有关，但我们和其他人最近证明了内皮细胞（EC）中存在膜相关的er，并且这一受体亚群的参与也可能有助于内皮细胞的有利分子特征。在这篇综述中，我们描述了EC中膜定位内质网的证据。我们讨论了它们的膜靶向特征，以及它们与经典er的不同之处。我们还描述了一种膜相关分子复合物的快速组装，该分子复合物由ER、c-Src和磷脂酰肌醇3-激酶（PI3K）的调控单元p85组成，以响应雌激素。最后，我们描述了该复合物如何触发包括内皮一氧化氮合酶（eNOS）在内的顺序酶激活，并随后增强NO的基础释放，NO是血管张力和“健康”血管的关键调节剂。(c) 2005爱思唯尔公司版权所有。
There is substantial interest in the effects of estrogen on the vascular wall, due to the marked gender difference in the incidence of clinically apparent coronary heart disease (CHD), when comparing premenopausal women with age-matched males. Recent randomized clinical trials unexpectedly failed to demonstrate a hormone replacement therapy (HRT) benefit for CHD secondary or primary prevention in postmenopausal women. There are several possible explanations for these findings, which have created a conundrum in light of the numerous potentially beneficial vascular effects of estrogen demonstrated at the cellular, molecular, and even animal model level. Clinical trials are ongoing, and the dissection of molecular pathways continues. Although estrogen receptors (ERs) are traditionally defined as ligand-activated transcriptional activators or repressors, a phenomenon certainly involved in some of estrogen's beneficial effects on vascular cells, we and others have recently demonstrated the presence of membrane-associated ERs in endothelial cells (EC), and that engagement of this subset of receptors may also contribute to the favorable molecular profile of the endothelium. In this review, we describe evidence for membrane-localized ERs in EC. We discuss features of their membrane targeting, and how they may differ from classical ERs. We also describe the rapid assembly of a membrane-associated molecular complex, comprised of ER, c-Src and the regulatory unit of phosphatidylinositol 3-kinase (PI3K), p85, in response to estrogen. Finally, we describe how this complex triggers sequential enzyme activation, involving endothelial nitric oxide synthase (eNOS), and consequent enhanced basal release of NO, a key modulator of vascular tone and 'healthy' blood vessels. (c) 2005 Elsevier Inc. All rights reserved.