Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.
Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.
J Cell Physiol. 2018 Sep;233(9):6644-6659. doi: 10.1002/jcp.26315. Epub 2018 Apr 10.
In ruminant, the receptive endometrium and the elongation of the hatched blastocyst are required to complete the process of implantation. However, the mechanisms regulating goat endometrial function during the peri-implantation period of pregnancy are still unclear. In this study, EECs were treated with progesterone, estradiol, and interferon-tau (IFNT). We have found that endoplasmic reticulum (ER) stress was activated under hormones treatment. To identify the cellular mechanism of regulation of endometrial function, we investigated the effect of ER stress activator thapsigargin (TG) and inhibitor 4 phenyl butyric acid (4-PBA) on EECs. We found that TG, which activated the three branches of UPR, increased the expression of genes associated with promoting conceptus elongation and cellular attachment, significantly up-regulated the spheroid attachment rate and PGE /PGF ratio. 4-PBA pre-treatment inhibited UPR and inhibited promoting conceptus elongation and cellular attachment related genes, but the spheroid attachment rate and PGE /PGF ratio were not changed significantly. Moreover, knockdown of ATF6 via shATF6 promoted the conceptus elongation related genes, but increased the dissolution of the corpus luteum. Besides, blocking ATF6 attenuated autophagy by activating mammalian target of rapamycin (mTOR) pathway. Moreover, rapamycin (mTOR inhibitor) pre-treatment inhibited the expression of promoting conceptus elongation and increased PGE /PGF ratio. Taken together, our study indicated that physiological level of ER stress may contribute to early pregnancy success, and ATF6 signaling pathway cooperated with autophagy to regulate endometrial function by modulating mTOR pathway.
在反刍动物中，接受性子宫内膜和孵化的囊胚伸长是完成植入过程所必需的。然而，妊娠植入期调节山羊子宫内膜功能的机制仍不清楚。在这项研究中，EEC 用孕酮、雌二醇和干扰素-tau（IFNT）处理。我们发现激素处理下内质网（ER）应激被激活。为了确定调节子宫内膜功能的细胞机制，我们研究了 ER 应激激活剂他普西醌（TG）和抑制剂 4-苯基丁酸（4-PBA）对 EEC 的影响。我们发现，激活 UPR 三个分支的 TG 增加了与促进胚胎伸长和细胞附着相关的基因的表达，显著提高了球体附着率和 PGE/PGF 比值。4-PBA 预处理抑制 UPR 并抑制与促进胚胎伸长和细胞附着相关的基因，但球体附着率和 PGE/PGF 比值没有明显变化。此外，通过 shATF6 敲低 ATF6 促进了胚胎伸长相关基因，但增加了黄体的溶解。此外，通过激活哺乳动物雷帕霉素靶蛋白（mTOR）途径抑制 ATF6 可抑制自噬。此外，雷帕霉素（mTOR 抑制剂）预处理抑制了促进胚胎伸长的表达并增加了 PGE/PGF 比值。总之，我们的研究表明，生理水平的 ER 应激可能有助于早期妊娠成功，ATF6 信号通路通过调节 mTOR 通路与自噬一起调节子宫内膜功能。
