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.

胚胎植入涉及一种无菌的炎症反应，这是囊胚侵入蜕膜所必需的。从受压或受损细胞释放的三磷酸腺苷 (ATP) 作为重要的信号分子来调节许多关键生理事件，包括无菌炎症。我们发现小鼠子宫腔液中的 ATP 量在围着床期增加，这取决于胚胎的存在。我们进一步表明，接受性上皮细胞释放 ATP 可能是由囊胚通过连接蛋白半通道释放的乳酸刺激的。ATP 受体 P2y2 在植入前阶段存在于子宫上皮细胞上，并在蜕膜开始时在基质细胞中增加。P2y2 的药理学抑制损害蜕膜化和植入。ATP-P2y2 信号刺激子宫腔上皮细胞中 Stat3 的磷酸化和早期生长反应 1 ( Egr1 ) 和前列腺素内过氧化物合酶 2 ( Ptgs2，也称为Cox-2)，所有这些都是基质细胞蜕膜化和/或植入所必需的。短时间暴露于高浓度 ATP 促进了原代基质细胞的蜕膜化，但长时间暴露或较低 ATP 浓度不会。在胚胎着床期间，蜕膜中编码 ATP 降解外核苷酸酶的基因表达增加，表明它们可能限制了 ATP 信号的持续时间。总之，我们的结果表明，在胚胎着床期间，囊胚诱导的子宫上皮细胞释放 ATP 可能对基质细胞蜕膜化的开始很重要。