Catecholestradiol Activation of Adrenergic Receptors Induces Endometrial Cell Survival via p38 MAPK Signaling

Sprague R, Rachel Sprague, Joung W. Kim, Esma Kirimlioglu, Esma Konuk, Guo X, Xiaofang Guo, Nihan Günay, Günay N, Ozlem Guzeloglu-Kayisli, Ozlem Guzeloglu‐Kayisli, Aslı Özmen, Ozmen A, Asli Ozmen, Frederick Schatz, Schatz F, Anthony N. Imudia, Imudia AN, Lockwood CJ, Charles J. Lockwood, Magness RR, Ronald R. Magness, Kayisli UA, Umit A. Kayisli
The Journal of clinical endocrinology and metabolism · 2020 · vol. 106(2) , pp. 337–350 · doi:10.1210/clinem/dgaa866 · PMID:33247592 · W3110220269
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Catecholestradiols activate ER-independent β-adrenergic receptors to promote endometrial cell survival via p38 MAPK signaling, suggesting potential therapeutic targets for endometriosis.

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Abstract

CONTEXT: Enhanced levels of catecholestradiols, 2-hydroxyestradiol (2-OHE2) or 4-hydroxyestradiol (4-OHE2), are reported in endometriosis. During gestation, catecholestradiol activation of adrenergic receptors (AR) elevates estrogen receptor (ER)-independent proliferation of uterine arterial endothelial cells. OBJECTIVE: To investigate β-AR-mediated catecholestradiol effects on human endometrial stromal cell (HESC) and epithelial cell survival in endometriosis. DESIGN: β-AR immunostaining of eutopic and ectopic endometria (n = 9). Assays for cell viability, 5-bromo-2'-deoxyuridine proliferation, apoptosis, quantitative PCR, and estrogenicity (alkaline phosphatase activity), as well as siRNA β-AR silencing and immunoblot analyses of cultured HESCs or Ishikawa cells treated with control or 2-OHE2 or 4-OHE2 ±β-AR antagonist or ±p38 MAPK inhibitor. SETTING: University research institution. PATIENTS: Women with or without endometriosis. INTERVENTIONS: None. MAIN OUTCOME MEASURES: β-AR expression in eutopic vs ectopic endometria and regulation of HESC survival by 2-OHE2 and 4-OHE2. RESULTS: Eutopic and ectopic endometrial stromal and epithelial cells displayed β2-AR immunoreactivity with increased staining in the functionalis vs basalis layer (P < 0.05). Both 2-OHE2 and 4-OHE2 enhanced HESC and Ishikawa cell survival (P < 0.05), an effect abrogated by β-AR antagonist propranolol, but not ER antagonist ICI182,780. 2-OHE2 or 4-OHE2 failed to induce cell survival and estrogenic activity in ADRB2-silenced HESCs and in Ishikawa cells, respectively. Although 2-OHE2 inhibited apoptosis and BAX mRNA expression, 4-OHE2 induced proliferation and decreased apoptosis (P < 0.05). Both catecholestradiols elevated phospho-p38 MAPK levels (P < 0.05), which was blocked by propranolol, and p38 MAPK inhibitor reversed catecholestradiol-enhanced HESC survival. CONCLUSIONS: Catecholestradiols increase endometrial cell survival by an ER-independent β-AR-mediated p38 MAPK activation, suggesting that agents blocking β-AR (e.g., propranolol) or inhibiting 2-OHE2- or 4-OHE2-generating enzymes (i.e., CYP1A1/B1) could treat endometriosis.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometrium Estrogens, Catechol p38 Mitogen-Activated Protein Kinases Receptors, Adrenergic Adult Adult Case-Control Studies Case-Control Studies Cell Proliferation Cell Proliferation Cell Survival Cell Survival Endometriosis Endometriosis Endometriosis Endometriosis Endometrium Endometrium Endometrium

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