Abnormal elevated PANX1 expression hampers endometrial decidualization by upregulating extracellular ATP concentration in patients with recurrent implantation failure

Recurrent implantation failure (RIF), a important contributor to infertility in assisted reproductive technologies, is believed to be primarily to abnormal endometrial decidualization. However, its related molecular mechanisms are still incompletely clear. It has been reported that PANX1 is an ATP-permeable channel to regulate the extracellular ATP, and ATP level could influence the progress of endometrial decidualization. Therefore, we conduct this study to explore the potential role of PANX1 during the development of RIF. In this study, we first compared the the expression of PANX1 in RIF patients and control patients. Then, the human endometrial stromal cells (HESCs) was used to the explore the regulatory function of PANX1 on endometrial decidualization by Immunofluorescence staining, Western blot, RT-PCR, Plasmid transfection and ATP detection. Finally, animal model was established to further confirm the results which were found in vitro. We observed a significant upregulation expression of ATP release channel protein Pannexin1 (PANX1) in endometrial tissue of RIF patients. Moreover, after overexpressing PANX1 in human endometrial stromal cells (HESCs), we found a significantly high concentration of extracellualr ATP (eATP) and the inhibition of HESCs decidualization, which was characterized as the decreasing expression of prolactin (PRL) and insulin-like growth factor binding protein 1 (IGFBP-1), as well as the aberrant morphologic cytoskeletion of HESCs. Surprisingly, knockdown the expression of PANX1 in HESCs also impaired the cellular decidualization, indicating the important role of normal PANX1 expression during the process of endometrial decidualization. The subsequent animal study further confirmed our findings in vitro. The present study clearly showed that abnormal high expression of PANX1 hindered endometrial decidualization through the upregulation of eATP concentrations, ultimately leading to embryo implantation failure. Our findings suggested a novel cause of RIF and identified a potential therapeutic target for RIF.