Fan Xiang, Wang Jing, Ma Yinyin, Chai Dandan, Han Suo, Xiao Chuyu, Huang Yingtong, Wang Xiaojie, Wang Jianming, Wang Shimeng, Xiao Li, Zhang Chunping
Department of Cell Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China.
Institute of Rehabilitation Science, Shaanxi Provincial Rehabilitation Hospital, Xi'an 710065, China.
Biology (Basel). 2024 Aug 15;13(8):620. doi: 10.3390/biology13080620.
Chronic stress has become a major problem that endangers people's physical and mental health. Studies have shown that chronic stress impairs female reproduction. However, the related mechanism is not fully understood. P2X7 receptor (P2X7R) is involved in a variety of pathological changes induced by chronic stress. Whether P2X7R is involved in the effect of chronic stress on female reproduction has not been studied. In this study, we established a chronic restraint stress mouse model and chronic cold stress mouse model. We found that the number of corpora lutea was significantly reduced in the two chronic stress models. The number of corpora lutea indirectly reflects the ovulation, suggesting that chronic stress influences ovulation. P2X7R expression was significantly increased in ovaries of the two chronic stress models. A superovulation experiment showed that P2X7R inhibitor A-438079 HCL partially rescued the ovulation rate of the two chronic stress models. Further studies showed that activation of P2X7R signaling inhibited the cumulus expansion and promoted the expression of NPPC in granulosa cells, one key negative factor of cumulus expansion. Moreover, sirius red staining showed that the ovarian fibrosis was increased in the two chronic stress models. For the fibrosis-related factors, TGF-β1 was increased and MMP2 was decreased. In vitro studies also showed that activation of P2X7R signaling upregulated the expression of TGF-β1 and downregulated the expression of MMP2 in granulosa cells. In conclusion, P2X7R expression was increased in the ovaries of the chronic restraint-stress and chronic cold-stress mouse models. Activation of P2X7R signaling promoted NPPC expression and cumulus expansion disorder, which contributed to the abnormal ovulation of the chronic stress model. Activation of P2X7R signaling is also associated with the ovarian fibrosis changes in the chronic stress model.
慢性应激已成为危害人们身心健康的主要问题。研究表明，慢性应激会损害女性生殖功能。然而，相关机制尚未完全明确。P2X7受体（P2X7R）参与了慢性应激诱导的多种病理变化。P2X7R是否参与慢性应激对女性生殖的影响尚未见研究报道。在本研究中，我们建立了慢性束缚应激小鼠模型和慢性冷应激小鼠模型。我们发现，在这两种慢性应激模型中，黄体数量显著减少。黄体数量间接反映排卵情况，提示慢性应激会影响排卵。在两种慢性应激模型的卵巢中，P2X7R表达显著增加。超排卵实验表明，P2X7R抑制剂盐酸A-438079可部分挽救两种慢性应激模型的排卵率。进一步研究表明，P2X7R信号通路的激活抑制了卵丘扩展，并促进了颗粒细胞中卵丘扩展关键负性因子NPPC的表达。此外，天狼星红染色显示，两种慢性应激模型中的卵巢纤维化均增加。对于纤维化相关因子，转化生长因子-β1（TGF-β1）增加，基质金属蛋白酶2（MMP2）减少。体外研究还表明，P2X7R信号通路的激活上调了颗粒细胞中TGF-β1的表达，下调了MMP2的表达。总之，在慢性束缚应激和慢性冷应激小鼠模型的卵巢中，P2X7R表达增加。P2X7R信号通路的激活促进了NPPC表达和卵丘扩展紊乱，这导致了慢性应激模型排卵异常。P2X7R信号通路的激活还与慢性应激模型中的卵巢纤维化变化有关。
