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

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.