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

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Abstract
Context Enhanced levels of catecholestradiols, 2-OHE2 or 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, BrdU proliferation, apoptosis, q-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 ±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 (P2 and 4-OHE2 enhanced HESC and Ishikawa cell survival (P2 or 4-OHE2 failed to induce cell survival and estrogenic activity in ADRB2-silenced HESCs and in Ishikawa cells, respectively. While 2-OHE2 inhibited apoptosis and BAX mRNA expression, 4-OHE2 induced proliferation and decreased apoptosis (P2- or 4-OHE2-generating enzymes (i.e., CYP1A1/B1) could treat endometriosis.

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