Abstract
Women experience menopause later in life. Menopause is characterized by dramatically decreased circulating estrogen level secondary to loss of ovarian function and atrophic state of genital organs. However, the molecular mechanisms for this process are not fully understood. In this study, we aimed to investigate the potential molecular mechanisms that underlie menopause-induced uterine endometrial atrophy. Our data showed that autophagy was activated in the uterine epithelial cells of both ovariectomized rats and peri-menopausal females. Endoplasmic reticulum (ER) stress occurred even prior to autophagy induction. Integrated bioinformatics analysis revealed that ER stress induced downstream decreased release of arachidonic acid (AA) and downregulation of AA/prostaglandin E2 (PGE2) axis, which led to Akt/mTOR signaling pathway inactivation. Consequently, autophagosomes were recruited and LC3-dependent autophagy was induced in uterine epithelial cells. Treatment with exogenous E2, PGE2, salubrinal or RNAi-mediated silencing of key autophagy genes could effectively counteract estrogen depletion-induced autophagy. Collectively, autophagy is a critical regulator of the uterine epithelium that accounts for endometrial atrophy after menopause.
Highlights
IntroductionThe accurate molecular mechanisms by which estrogen interferes with cytokine activity are still unelucidated but may potentially include interactions of the Endoplasmic reticulum (ER) with other transcription factors, modulation of nitric oxide activity, antioxidative effects, plasma membrane actions, and alterations in immune cell function[1]
48 h were analyzed for LC3 using immunofluorescent analysis. (d) Quantification of acridine orange (AO)-positive autophagosomes in epithelial cells (EECs) treated with DMSO, E2, letrozole or letrozole +E2 from Fig. 1i. (e) Quantification of GFP-LC3 dots in EECs treated with DMSO, E2, letrozole or letrozole +E2 from Fig. 1j. (f) Quantification of LC3positive dots in EECs treated with DMSO, E2, letrozole or letrozole +E2 from Fig. 1j. (g) Conversion of
These findings demonstrated that autophagy might be activated in the uterine epithelium after estrogen withdrawal
Summary
The accurate molecular mechanisms by which estrogen interferes with cytokine activity are still unelucidated but may potentially include interactions of the ER with other transcription factors, modulation of nitric oxide activity, antioxidative effects, plasma membrane actions, and alterations in immune cell function[1]. These molecular mechanisms could not explain the atrophic state of genital organs and tissues like uterine endometrium after menopause. We uncovered a critical role of autophagy as a regulator of the uterine endometrial atrophy after menopause in women
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