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Estrogen Regulates Endoplasmic Reticulum Stress–Mediated Apoptosis by ERK-p65 Pathway to Promote Endometrial Angiogenesis

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Abstract

Estrogen (17β-oestradiol, E2) plays an essential role in endometrial receptivity and has been shown to stimulate angiogenesis via E2-ERα (estrogen receptor)-mediated upregulation of VEGF transcription. In this study, we have tried to decipher the mechanism of E2-promoting angiogenesis. We pre-incubated human endometrial microvascular endothelial cells (HEMECs) with E2 and performed western blotting, qRT-PCR, and cellular immunofluorescence experiments. We observed that E2 treatment of HEMECs increased ERα expression and reduced the expression of GRP78, which led to reduction of Caspase 3 expression by the CHOP pathway. In addition, E2 not only activated ERK signaling pathway but also inhibited p65 phosphorylation along with its translocation from nucleus to the cytoplasm, and subsequently inhibiting GRP78 expression, which led to inhibition of cell apoptosis. Together, these findings highlight the novel mechanism underlying E2-mediated improvement in endometrial angiogenesis through the ERK-p65 signaling pathway.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.

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Funding

The study was supported by the National Natural Science Foundation of China (No. 82074247, No. 81603654), the Department of Education of Hebei Province (No. ZD2018002, No. QN2019153), and the Foundation of Scientific Research Program of Hebei Administration of Traditional Chinese Medicine (No. 2018098).

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  1. Yu Zhang and Can Cao contributed equally to this work.

Authors and Affiliations

  1. Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, 3 Xing Yuan Road, Luquan, Shijiazhuang, China

    Yu Zhang, Can Cao, Shujin Du, Lijie Fan, Dong Zhang, Xiangting Wang & Ming He

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  1. Yu Zhang
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Contributions

As the corresponding author, MH contributed to the statistical analysis and prepared the manuscript for writing, and XTW contributed to the conception and design of the study. YZ contributed to the statistical analysis. CC was responsible for the cell culture and treatment. SJD performed the western blot analysis and endothelial cell tube formation assay. LJF contributed to the isolation of mRNA and qRT-PCR. DZ performed the immunofluorescence staining.

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Correspondence to Xiangting Wang or Ming He.

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Zhang, Y., Cao, C., Du, S. et al. Estrogen Regulates Endoplasmic Reticulum Stress–Mediated Apoptosis by ERK-p65 Pathway to Promote Endometrial Angiogenesis. Reprod. Sci. 28, 1216–1226 (2021). https://doi.org/10.1007/s43032-020-00414-0

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