VEGF signaling is disrupted in the hearts of mice lacking estrogen receptor alpha
VEGF signaling is disrupted in the hearts of mice lacking estrogen receptor alpha
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DOI：
10.1016/j.ejphar.2010.05.020
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发表时间：
2010-09-01
影响因子：
5
通讯作者：
Kobayashi, Hiroyuki
中科院分区：
文献类型：
--
作者：
Jesmin, Subrina;Mowa, Chishimba N.;Kobayashi, Hiroyuki
雌激素被广泛认为对女性的心脏有保护作用。然而，这些有益的雌激素作用的确切机制尚未完全了解。在这方面，我们力求：1）阐明雌激素对血管内皮生长因子（VEGF）水平的影响，VEGF是心血管过程的关键调节因子，以及心脏中基本信号机制（VEGF受体，Akt和eNOS）的组成部分，以及2）使用缺乏雌激素受体α或雌激素受体β的小鼠描绘介导其有益作用的特定雌激素受体信号通路。我们分析了野生型（WT）、雌激素受体α敲除（ER α-KO）和雌激素受体β敲除（ER β-KO）雌性小鼠心脏中VEGF信号传导模式和相关的冠状动脉毛细血管密度。与野生型（WT）小鼠相比，雌激素受体α的缺失导致冠状动脉毛细血管密度显著降低，而雌激素受体β的缺失影响最小。与冠状动脉毛细血管密度降低一致，ER α-KO小鼠中VEGF及其信号分子（两种受体，磷酸化Akt和eNOS）的心脏表达水平降低至WT的一半，而ER β-KO小鼠仅显示轻微降低。此外，eNOS的活性在ER α-KO小鼠中大大降低。这些数据表明，雌激素主要通过雌激素受体α来调节VEGF转录及其基本信号传导的可能组分，并最终调节心脏中冠状动脉微血管的发育。这些分子和组织学数据，在一定程度上，揭示了雌激素心脏保护作用的潜在机制。(C)2010 Elsevier B. V.保留所有权利。
Estrogen has widely been credited for cardioprotection in women. However, the exact mechanisms that underlie these beneficial estrogenic effects are not completely understood. Here, we sought to: 1) elucidate estrogen's influence on levels of vascular endothelial growth factor (VEGF), a key regulator of cardiovascular processes, and components of its basic signaling machinery (VEGF receptors, Akt, and eNOS) in the heart, and 2) delineate the specific estrogen receptor signaling pathway that mediates its beneficial effects using mice lacking either estrogen receptor alpha or estrogen receptor beta. We analyzed pattern of VEGF signaling and the associated coronary capillary density in the hearts of wild-type (WT), estrogen receptor alpha knockout (ER alpha-KO), and estrogen receptor beta knockout (ER beta-KO) female mice. Deletion of estrogen receptor alpha causes a marked decrease in coronary capillary density compared to wild-type (WT) mice, while that of estrogen receptor beta had a minimal effect. Consistent with reduced coronary capillary density, cardiac expression levels of VEGF and its signaling molecules (two receptors, phosphorylated Akt, and eNOS) in ER alpha-KO mice were reduced to half of WT, in contrast to ER beta-KO mice that only showed a slight decrease. Moreover, activity of eNOS was greatly lowered in ER alpha-KO mice. These data suggest that estrogen acts largely via estrogen receptor alpha to regulate VEGF transcription and possibly components of its basic signaling and ultimately, the development of coronary microvasculature in the heart. This molecular and histological data, in part, sheds some insights into potential mechanisms that may likely underlie estrogen's cardioprotective effects. (C) 2010 Elsevier B.V. All rights reserved.