Annexin A7 Regulates Endometrial Receptivity.

Md Alauddin,Jan J Brosens,Anna Wagner,Anja T Umbach,Sara Y Brucker,Diethelm Wallwiener,Florian Lang,Madhuri S Salker,Toshiyuki Okumura,Yogesh Singh,Janet Rajaxavier

doi:10.3389/fcell.2020.00770

Abstract

A limited window of receptivity is a prerequisite of reproductive success. Indispensable receptivity genes include cyclooxygenase 2 (COX2), an enzyme accomplishing formation of prostaglandin E2 (PGE2). A powerful regulator of PGE2 formation is Annexin A7 (ANXA7). The present study thus explored whether ANXA7 impacts on implantation and fertility. Here we show that ANXA7 is expressed in endometrial tissue and increases upon decidual transformation of human endometrial stromal cells (HESCs) in a time-dependent manner. Silencing ANXA7 significantly decreased the expression of PRL and IGFBP1, canonical decidual marker genes, but enhances COX2 and PGE2 levels. Genetic knockout of AnxA7 in mice significantly increases the number of implantation sites and litter sizes. Further, analysis of human endometrial biopsies showed that ANXA7 transcript and protein levels are decreased during the midluteal window of implantation in women suffering from recurrent pregnancy loss (RPL) when compared to subfertile patients. Taken together, the data indicate that ANXA7 has a conserved role in regulating endometrial receptivity and implantation.

Highlights

Following the post-ovulatory rise in progesterone levels, human endometrial stromal cells (HESCs) undergo extensive biochemical and morphological reprogramming, a process known as decidualization, in preparation for pregnancy (Koot et al, 2012; Gellersen and Brosens, 2014)
We demonstrated that Annexin A7 (ANXA7) knockdown impairs the induction of cardinal decidual markers prolactin (PRL) and insulin-like growth factor binding protein 1 (IGFBP1), but enhances cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) levels in human endometrium
Analysis of independent primary cultures demonstrated that ANXA7 remained low during the initial pro-inflammatory decidual phase (Salker et al, 2012a; Lucas et al, 2020) before rising around days 6–8, which coincides with the emergence of specialized decidual cells (Salker et al, 2012a; Lucas et al, 2020; Figures 1B,C and Supplementary Figure S1)

Summary

Introduction

Following the post-ovulatory rise in progesterone levels, human endometrial stromal cells (HESCs) undergo extensive biochemical and morphological reprogramming, a process known as decidualization, in preparation for pregnancy (Koot et al, 2012; Gellersen and Brosens, 2014) While this process is initiated during the mid-luteal phase of the cycle, the emergence of morphologically decidualized cells at the start of the late-luteal phase marks the end of the implantation window, defined as the limited period during which a developmentally competent blastocyst can implant (Cha et al, 2012; Koot et al, 2012; Gellersen and Brosens, 2014; Macklon and Brosens, 2014). Loss of COX2 or PLA2 can result in infertility due to abnormalities of ovulation, implantation, and decidualization in mice (Lim et al, 1997; Vilella et al, 2013; Salker et al, 2018)

Methods

Results

Conclusion