Activation of the epithelial Na⁺channel triggers prostaglandin E₂release and production required for embryo implantation

Embryo implantation remains a poorly understood process. We demonstrate here that activation of the epithelial Na+channel (ENaC) in mouse endometrial epithelial cells by an embryo-released serine protease, trypsin, triggers Ca2+influx that leads to prostaglandin E2(PGE2) release, phosphorylation of the transcription factor CREB and upregulation of cyclooxygenasE2, the enzyme required for prostaglandin production and implantation. We detected maximum ENaC activation, as indicated by ENaC cleavage, at the time of implantation in mice. Blocking or knocking down uterine ENaC in mice resulted in implantation failure. Furthermore, we found that uterine ENaC expression before in vitro fertilization (IVF) treatment is markedly lower in women with implantation failure as compared to those with successful pregnancy. These results indicate a previously undefined role of ENaC in regulating the PGE2production and release required for embryo implantation, defects that may be a cause of miscarriage and low success rates in IVF.