ALK3-SMAD1/5 Signaling Mediates the BMP2-Induced Decrease in PGE2 Production in Human Endometrial Stromal Cells and Decidual Stromal Cells.

Peter C. K. Leung,Yu Zhang,Hua Zhu,Hsun-Ming Chang

doi:10.3389/fcell.2020.573028

Abstract

BMP2 is a critical factor that is involved in the processes of embryo implantation and uterine decidualization. The expression of cyclooxygenase (COX) and subsequent prostaglandin E2 (PGE2) production are critical for successful pregnancy. However, it is not clear whether BMP2 can regulate the production of PG during endometrial decidualization. The aim of this study was to investigate the effects of BMP2 on COX-1 expression and PGE2 production as well as the underlying molecular mechanisms in the human endometrium. Immortalized human endometrial stromal cells (HESCs) and human decidual stromal cells (HDSCs) were used as the study model to investigate the effects of BMP2-induced cellular activities. Our results showed that BMP2 treatment significantly decreased PGE2 production by downregulating COX-1 expression in both human endometrial stromal and decidual stromal cells. Additionally, BMP2 induced an increase in the levels of phosphorylated SMAD1/5/8, and this effect was completely abolished by the addition of the inhibitors DMH-1 and dorsomorphin, but not by SB431542. Knocking down ALK3 completely reversed the BMP2-induced downregulation of COX-1. Moreover, concomitantly knocking down SMAD1 and SMAD5 completely reversed the BMP2-induced downregulation of COX-1. Our results indicated that BMP2 decreased PGE2 production by downregulating COX-1 expression, most likely through the ALK3/SMAD1-SMAD5 signaling pathway in human endometrial stromal and human decidual stromal cells. These findings deepen our understanding of the functional role of BMP2 in the regulation of endometrial decidualization in humans.

Highlights

At the maternal-fetal interface, human pregnancy is a complex developmental event involving in multiple processes, including endometrial decidualization, the acquisition of an immunologic phenotype and a series of inflammatory-type responses (Salamonsen et al, 2000; Dey et al, 2004, Lobo et al, 2004; Yoshinaga, 2008)
BMP2 Downregulates the Expression of COX-1 in human endometrial stromal cells (HESCs) and human decidual stromal cells (HDSCs) To test the hypothesis that BMP2 regulates the synthesis of prostaglandin E2 (PGE2), we first investigated the effect of BMP2 on the expression of COX-1 in HESCs and HDSCs
To investigate whether BMP2 activates Sma- and Mad-related (SMAD) signaling in HESCs and HDSCs, we treated the cells with exogenous BMP2 (25 ng/mL) for 10, 30, 60 or 120 min

Summary

Introduction

At the maternal-fetal interface, human pregnancy is a complex developmental event involving in multiple processes, including endometrial decidualization, the acquisition of an immunologic phenotype and a series of inflammatory-type responses (Salamonsen et al, 2000; Dey et al, 2004, Lobo et al, 2004; Yoshinaga, 2008). During the early stage of human pregnancy, the concentrations of PGs in the decidua are significantly lower than those in the endometrium in all stages of the menstrual cycle (Abel et al, 1980). The expression of COX-1 is constitutive, the concentration of COX-1 fluctuates during the menstrual cycle and throughout the gestation period. The concentration of COX-1 is precipitously decreased in the midluteal phase of the menstrual cycle in preparation for implantation and during decidualization periods (Marions and Danielsson, 1999; St-Louis et al, 2010). The regulatory mechanism of each COX enzyme, especially COX-1, and subsequent PG synthesis during the menstrual cycle and early pregnancy in the human uterus remain to be elucidated

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