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ER Alpha Rapid Signaling Is Required for Estrogen Induced Proliferation and Migration of Vascular Endothelial Cells.

ABSTRACT: 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 (ER?). ER? 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 ER? 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 ER? (KRR ER?) 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 ER?, 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 ER?, however, lack all of these responses. These observations establish KRR ER? as a novel tool that could greatly facilitate future studies into the vascular and non-vascular functions of ER? rapid signaling. Further, they support that rapid signaling through ER? is essential for many of the transcriptional and physiological responses of ECs to E2, and that ER? rapid signaling in ECs, in vivo, may be critical for the vasculoprotective and anti-inflammatory effects of estrogen.

SUBMITTER: Lu Q

PROVIDER: S-EPMC4818104 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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ER Alpha Rapid Signaling Is Required for Estrogen Induced Proliferation and Migration of Vascular Endothelial Cells.

Lu Qing Q Schnitzler Gavin R GR Ueda Kazutaka K Iyer Lakshmanan K LK Diomede Olga I OI Andrade Tiffany T Karas Richard H RH

PloS one 20160401 4

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 recent ...[more]

PMID: 27035664

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Project description:Background: Clinical trial and epidemiological data support that the cardiovascular effects of estrogen are complex, including a mixture of both potentially beneficial and harmful effects. In animal models, estrogen protects females from vascular injury and inhibits atherosclerosis. These effects are mediated by estrogen receptors (ERs), which when bound to estrogen can bind to DNA to directly regulate transcription. ERs can also activate several cellular kinases by inducing a M-bM-^@M-^\rapidM-bM-^@M-^] non-nuclear signaling cascade. However, the biologic significance of this rapid signaling pathway has been unclear. Methods and Results: Here, we develop a novel transgenic mouse in which rapid signaling is blocked by over-expression of a peptide that prevents ERs from interacting with the scaffold protein, striatin (the Disrupting Peptide Mouse, DPM). Microarray analysis of ex vivo-treated mouse aortas demonstrates that rapid ER signaling plays an important role in E2-mediated gene regulatory responses. Disruption of ER-striatin interactions also eliminates the ability of E2 to stimulate cultured endothelial cell migration and to inhibit cultured vascular smooth muscle cell growth. The importance of these findings is underscored by in vivo experiments demonstrating loss of estrogen-mediated protection against vascular injury in the DPM mouse following carotid artery wire injury. Conclusions: Taken together, these results support that rapid, non-nuclear ER signaling contributes to the transcriptional regulatory functions of ER, and is essential for many of the vasoprotective effects of estrogen. These findings also identify the rapid ER signaling pathway as a potential target for the development of novel therapeutic agents. Transgenic disrupting peptide mice (DPM) express the Estrogen Receptor (ER) alpha amino acids 176-253 peptide under CMV promoter control. This peptide blocks interactions between ER and striatin, which inhibits rapid non-genomic signaling by ER to cellular kinases. Female WT and DPM mice (4 mice per sample) were overiectomized, and 1 week later aortas were harvested and treated + 10 nM beta-estradiol (E2) or + EtOH vehicle (Veh) for 4 hrs ex vivo. Total RNA was collected, reverse transcribed to cDNA and used to probe Affymetrix mouse 430.A 2.0 arrays.

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ER Alpha Rapid Signaling Is Required for Estrogen Induced Proliferation and Migration of Vascular Endothelial Cells.

Publications

ER Alpha Rapid Signaling Is Required for Estrogen Induced Proliferation and Migration of Vascular Endothelial Cells.

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