Abstract
Local renin-angiotensin system (RAS) in female reproductive system is involved in many physiological and pathological processes, such as follicular development, ovarian angiogenesis, ovarian, and endometrial cancer progress. However, studies on the functional relevance of RAS in human endometrium are limited, especially for renin-angiotensin-aldosterone system (RAAS). In this study, we defined the location of RAS components in human endometrium. We found that angiotensin II type-1 receptor (AT1R) and aldosterone synthase (CYP11B2), major components of RAAS, are specifically expressed in endometrial gland during mid-secretory phase. Aldosterone receptor, mineralocorticoid receptor (MR), is elevated in stroma in mid-secretory endometrium. In vitro, MR is also activated by aldosterone during decidualization. Activated MR initiates LKB1 expression, followed by phosphorylating of AMPK that stimulates PDK4 expression. The impact of PDK4 on decidualization is independent on PDHE1α inactivation. Based on co-immunoprecipitation, PDK4 interacts with p-CREB to prevent its ubiquitination for facilitating decidualization via FOXO1. Restrain of MR activation interrupts LKB1/p-AMPK/PDK4/p-CREB/FOXO1 pathway induced by aldosterone, indicating that aldosterone action on decidualization is mainly dependent on MR stimulation. Aldosterone biosynthesized in endometrial gland during mid-secretory phase promotes decidualization via activating MR/LKB1/p-AMPK/PDK4/p-CREB/FOXO1 signaling pathway. This study provides the valuable information for understanding the underlying mechanism during decidualization.
Highlights
Successful pregnancy requires embryo implantation into a receptive endometrium and subsequent decidualization in rodents and primates[1,2]
We discovered the presence of local reninangiotensin-aldosterone system (RAAS) in glandular epithelium during the mid-secretory phase of menstrual cycle and found that aldosterone activates Liver kinase B1 (LKB1)-p-AMPKPDK4-p-cAMP response element-binding protein (CREB)-FOXO1 signaling during decidualization
Immunohistochemistry was used to analyze the expressions of RENIN, angiotensin converting enzyme (ACE), angiotensin II type-1 receptor (AT1R) and CYP11B2 in human endometrium
Summary
Successful pregnancy requires embryo implantation into a receptive endometrium and subsequent decidualization in rodents and primates[1,2]. Human reproduction is remarkably inefficient, with only 13–14% chance for natural conception per menstrual cycle[2]. Nearly 30% of pregnancy ends in pregnancy loss[3,4]. Epithelial glands are essential for establishment of uterine receptivity and stromal decidualization[2,5,6]. Decidualization is one indispensable process during successful pregnancy[1,2]. Defective decidualization can result in College of Veterinary Medicine, South China Agricultural University, Department of Reproductive Endocrinology, Women’s Hospital, School of Medicine, Zhejiang University, Xueshi Road, Hangzhou 310006, China
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