ER Alpha Rapid Signaling Is Required for Estrogen Induced Proliferation and Migration of Vascular Endothelial Cells.
ER Alpha Rapid Signaling Is Required for Estrogen Induced Proliferation and Migration of Vascular Endothelial Cells.
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DOI：
10.1371/journal.pone.0152807
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Karas RH
中科院分区：
文献类型：
--
作者：
Lu Q;Schnitzler GR;Ueda K;Iyer LK;Diomede OI;Andrade T;Karas RH
雌激素促进血管内皮细胞（EC）的增殖和迁移，这可能是其加速再内皮化和减少血管损伤后不良重塑能力的基础。在之前的研究中，我们已经证明E2（雌激素的活性内源形式）对血管损伤的保护作用需要雌激素受体α（ERα）。 ERα 通过经典的 DNA 结合、“基因组”信号传导途径以及最近描述的由位于细胞膜的 ERα 子集介导的“快速”信号传导途径来转导雌激素的作用。然而，这些途径中哪一条介导雌激素对内皮细胞的影响尚不清楚。在这里，我们鉴定了 ERα (KRR ERα) 的三点突变版本，它在快速信号传导方面存在特殊缺陷，但能够通过“基因组”途径调节转录。我们发现在表达野生型ERα的EC中，E2调节许多参与细胞迁移和增殖的基因，促进EC迁移和增殖，并且还阻断单核细胞与EC的粘附。然而，表达 KRR 突变体 ERα 的 EC 缺乏所有这些反应。这些观察结果使 KRR ERα 成为一种新工具，可以极大地促进未来对 ERα 快速信号传导的血管和非血管功能的研究。此外，他们支持通过 ERα 的快速信号传导对于 EC 对 E2 的许多转录和生理反应至关重要，并且体内 EC 中的 ERα 快速信号传导可能对雌激素的血管保护和抗炎作用至关重要。
Estrogen promotes the proliferation and migration of vascular endothelial cells (ECs), which likely underlies its ability to accelerate re-endothelialization and reduce adverse remodeling after vascular injury. In previous studies, we have shown that the protective effects of E2 (the active endogenous form of estrogen) in vascular injury require the estrogen receptor alpha (ERα). ERα transduces the effects of estrogen via a classical DNA binding, “genomic” signaling pathway and via a more recently-described “rapid” signaling pathway that is mediated by a subset of ERα localized to the cell membrane. However, which of these pathways mediates the effects of estrogen on endothelial cells is poorly understood. Here we identify a triple point mutant version of ERα (KRR ERα) that is specifically defective in rapid signaling, but is competent to regulate transcription through the “genomic” pathway. We find that in ECs expressing wild type ERα, E2 regulates many genes involved in cell migration and proliferation, promotes EC migration and proliferation, and also blocks the adhesion of monocytes to ECs. ECs expressing KRR mutant ERα, however, lack all of these responses. These observations establish KRR ERα as a novel tool that could greatly facilitate future studies into the vascular and non-vascular functions of ERα rapid signaling. Further, they support that rapid signaling through ERα is essential for many of the transcriptional and physiological responses of ECs to E2, and that ERα rapid signaling in ECs, in vivo, may be critical for the vasculoprotective and anti-inflammatory effects of estrogen.