Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

Abstract

Estrogens are thought to promote labor by increasing the expression of pro-contraction genes in myometrial cells. The specific estrogen receptors ((ERs: ERa and ERb (also known as ESR1 and ESR2)) and G protein-coupled receptor 30 (GPR30; also known as G protein-coupled estrogen receptor 1)) and signaling pathways that mediate these actions are not clearly understood. In this study, we identified the ERs expressed in the pregnant human myometrium and determined a key extranuclear signaling pathway through which estradiol (E 2 ) modulates expression of the gene encoding the oxytocin receptor (OXTR), a major pro-contraction protein. Using quantitative RT-PCR, we found that ERa and GPR30 mRNAs were expressed in the human pregnant myometrium while ERb mRNA was virtually undetectable. While mRNA encoding ERa was the predominant ER transcript in the pregnant myometrium, ERa protein was largely undetectable in myometrial tissue by immunoblotting. Pharmacological inhibition of 26S proteasome activity increased ERa protein abundance to detectable levels in term myometrial explants, however, indicating rapid turnover of ERa protein by proteasomal processing in the pregnant myometrium. E 2 stimulated rapid extranuclear signaling in myometrial explants, as evidenced by increased extracellularly regulated kinase (ERK1/2) phosphorylation within 10 min. This effect was inhibited by pre-treatment with an ER antagonist, ICI 182 780, indicating the involvement of ERa. Inhibition of ERK signaling abrogated the ability of E 2 to stimulate OXTR gene expression in myometrial explants. We conclude that estrogenic actions in the human myometrium during pregnancy, including the stimulation of contraction-associated gene expression, can be mediated by extranuclear signaling through ERa via activation of the ERK/mitogen-activated protein kinase pathway.

Activation of the MAPK/ERK Cell-Signaling Pathway in Uterine Smooth Muscle Cells of Women With Adenomyosis

“…24 The MAPK/ERK pathway has also been studied in gravid uSMCs for its role in the mediation of estrogenic actions though ER-a in contraction-associated gene expression. 40,41 There are no specific ERK1/2 inhibitors. In the present study, we used the selective Mek MAPK kinase 1/2 inhibitor U0126 to study the effect of Mek MAPK kinase inhibition on proliferation of uSMCs.…”

Molecular Regulation of Parturition: A Myometrial Perspective

“…Furthermore, increased circulating E 2 levels (Challis 1971;Buster et al 1979) and enhanced ERa activity (Wu et al 1995;Mesiano et al 2002;Mesiano and Welsh 2007;Welsh et al 2012) near term also promote a cascade of proinflammatory events leading to the decline in PR function and parturition. Estrogens induce an influx of macrophages and neutrophils into the uterus and antagonize the anti-inflammatory actions of P 4 / PR (Tibbetts et al 1999;Mesiano et al 2002).…”

Overview of the mechanisms of induction of labor

“…Near term, however, the ratio of estrogen to progesterone increases, impacting regulatory function and causing a shift in the role of estrogen. 11,12 In concert with progesterone withdrawal, an increasing concentration of estrogen is thought to facilitate parturition. 11 Under the regulation of progesterone and estrogen, oxytocin is often synonymously associated with labor induction and augmentation.…”

“…11,12 In concert with progesterone withdrawal, an increasing concentration of estrogen is thought to facilitate parturition. 11 Under the regulation of progesterone and estrogen, oxytocin is often synonymously associated with labor induction and augmentation. Progesterone has been shown to suppress the oxytocin-induced production of prostaglandins and myometrial response to oxytocin, 13 whereas oxytocin receptor expression is enhanced by estrogen.…”