Blastocyst-induced ATP release from luminal epithelial cells initiates decidualization through the P2Y2 receptor in mice

Abstract

Embryo implantation involves a sterile inflammatory reaction that is required for the invasion of the blastocyst into the decidua. Adenosine triphosphate (ATP) released from stressed or injured cells acts as an important signaling molecule to regulate many key physiological events, including sterile inflammation. We found that the amount of ATP in the uterine luminal fluid of mice increased during the peri-implantation period, and this depended on the presence of an embryo. We further showed that the release of ATP from receptive epithelial cells was likely stimulated by lactate released from the blastocyst through connexin hemichannels. The ATP receptor P2y2 was present on uterine epithelial cells during the preimplantation period and increased in the stromal cells during the time at which decidualization began. Pharmacological inhibition of P2y2 compromised decidualization and implantation. ATP-P2y2 signaling stimulated the phosphorylation of Stat3 in uterine luminal epithelial cells and the expression of early growth response 1 (Egr1) and prostaglandin-endoperoxide synthase 2 (Ptgs2, also known as Cox-2), all of which are required for decidualization and/or implantation, in stromal cells. Short exposure to high concentrations of ATP promoted decidualization of primary stromal cells, but longer exposures or lower ATP concentrations did not. The expression of genes encoding ATP-degrading ectonucleotidases increased in the decidua during the peri-implantation period, suggesting that they may limit the duration of the ATP signal. Together, our results indicate that the blastocyst-induced release of ATP from uterine epithelial cells during the peri-implantation period may be important for the initiation of stromal cell decidualization.

Regulation and Function of Laminin A5 during Mouse and Human Decidualization

“…Our results showed that the disappearance of laminin A5 from the subepithelial basement membrane at the implantation site might be evidence that the embryo will be implanted through invading basement membrane. Signal transducer and activator of transcription 3 (STAT3), a marker of mouse uterine receptivity, is crucial for embryo implantation and decidualization [ 43 ]. Laminin α5β2γ1 enhances colorectal cancer cell self-renewal through STAT3 activation [ 44 ].…”

“…Mouse endometrial stromal cells were isolated and treated as previously described [ 43 ]. In brief, mouse uteri on day 4 were split longitudinally and digested with 6 mg/mL dispase II (Roche Applied Science, Indianapolis, IN) and 1% trypsin (Amresco, Cleveland, OH) in HBSS (Sigma-Aldrich).…”

“…RT-qPCR was performed as previously described [ 43 ]. Total RNAs were extracted using AG RNAex Pro Reagent (Accurate Biotechnology, Hunan, China) and reverse-transcribed into cDNA with HiScript II Q RT SuperMix for qPCR (Vazyme Biotech Co., Ltd., Nanjing, China).…”

In situ Synthesized Monosodium Urate Crystal Enhances Endometrium Decidualization via Sterile Inflammation During Pregnancy

“…In previous studies, we and others have shown that the endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) processes are associated with decidualization and act as inducers of the sterile inflammatory response during the implantation period ( Gu et al, 2016 ; Soczewski et al, 2020 ). We also reported that extracellular ATP induces decidualization of endometrial stromal cells via IL-8 in humans and mice ( Gu et al, 2020a , b ). However, to our knowledge, serum UA levels during the very early gestation stage have not yet been reported, and the role of MSU crystal, a well-known sterile inflammatory mediator, during the process of decidualization is still unknown.…”

A proteomic atlas of ligand–receptor interactions at the ovine maternal–fetal interface reveals the role of histone lactylation in uterine remodeling

“…This article contains supporting information ( 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 ).…”