Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
Nat Med. 2012 Jul;18(7):1112-7. doi: 10.1038/nm.2771.
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 cyclooxygenase 2, 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 PGE₂ production and release required for embryo implantation, defects that may be a cause of miscarriage and low success rates in IVF.
胚胎着床仍然是一个了解甚少的过程。我们在这里证明，胚胎释放的丝氨酸蛋白酶胰蛋白酶激活小鼠子宫内膜上皮细胞中的上皮钠离子通道（ENaC），引发钙内流，导致前列腺素 E₂（PGE₂）释放、转录因子 CREB 的磷酸化以及环氧化酶 2 的上调，环氧化酶 2 是产生前列腺素和着床所必需的酶。我们在小鼠的着床时检测到最大的 ENaC 激活，如 ENaC 切割所表明的那样。在小鼠中阻断或敲低子宫 ENaC 会导致着床失败。此外，我们发现，与成功妊娠的妇女相比，体外受精（IVF）治疗前具有着床失败的妇女的子宫 ENaC 表达明显降低。这些结果表明 ENaC 在调节胚胎着床所需的 PGE₂ 产生和释放方面具有以前未定义的作用，这些缺陷可能是流产和 IVF 成功率低的原因。
