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

Rachel Sprague, Joung W Kim, Esma Kirimlioglu, Esma Konuk, Xiaofang Guo, Nihan Günay, Ozlem Guzeloglu-Kayisli, Ozlem Guzeloglu‐Kayisli, Asli Ozmen, Aslı Özmen, Frederick Schatz, Anthony N Imudia, Charles J Lockwood, Ronald R Magness, 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
article OA: bronze CC0 ⤵ 3 in-corpus citations
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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

mesh:D004715endometriosis

MeSH descriptors

Endometriosis Endometrium Estrogens, Catechol p38 Mitogen-Activated Protein Kinases Receptors, Adrenergic Adult Case-Control Studies Cell Proliferation Cell Survival Endometriosis Endometriosis Endometriosis Endometrium Endometrium Estrogens, Catechol Female Follow-Up Studies Humans Middle Aged p38 Mitogen-Activated Protein Kinases

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