Research ArticleReproductive Biology

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

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Science Signaling  25 Aug 2020:
Vol. 13, Issue 646, eaba3396
DOI: 10.1126/scisignal.aba3396

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ATP stimulates embryo implantation

Decidualization is the process through which the uterine lining is remodeled to enable embryo implantation, which, in mice, depends on the presence of a blastocyst. Gu et al. found that uterine epithelial cells released ATP when a blastocyst was present and that ATP-mediated activation of the purinergic receptor P2Y2 induced decidualization markers and promoted embryo implantation. Experiments in vivo, in primary mouse uterine cells, and in cultured human uterine cells were consistent with ectonucleotidases in the uterine stroma limiting ATP signaling to restrict decidualization and implantation to a short window of time. These findings shed light on the blastocyst-uterine interactions that mediate the establishment of pregnancy.

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.

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