Activation of P2X7 Receptor Mediates the Abnormal Ovulation Induced by Chronic Restraint Stress and Chronic Cold Stress

• Published in: Biology (Basel, Switzerland) Vol. 13; no. 8; p. 620
• Main Authors: Fan, Xiang, Wang, Jing, Ma, Yinyin, Chai, Dandan, Han, Suo, Xiao, Chuyu, Huang, Yingtong, Wang, Xiaojie, Wang, Jianming, Wang, Shimeng, Xiao, Li, Zhang, Chunping
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.08.2024; MDPI
• Subjects: Analysis; Animal models; Cell activation; Cell culture; chronic cold stress; chronic restraint stress; Clemastine; Cold; corpus luteum; Down-regulation; Economic indicators; Ethanol; Females; Fibrosis; Follicles; Gelatinase A; Granulosa cells; Homeostasis; Mental disorders; Mental health; Ovaries; Ovulation; P2X7R; Penicillin; Physiological aspects; Reproduction; Reproductive health; Transforming growth factor-b1; Transforming growth factors; China; United States > US
• ISSN: 2079-7737; 2079-7737
• DOI: 10.3390/biology13080620

Chronic stress significantly impacts physical and mental health and has also been shown to affect female reproduction, but the underlying mechanisms are not well understood. Our research focused on the P2X7 receptor, a protein involved in the pathological response under long-term stress. Using mouse models subjected to chronic restraint and cold stress, we observed reduced ovulation rates, a key indicator of reproductive health. We discovered that stress increases the expression of the P2X7 receptor in the ovaries. Treatment with P2X7R inhibitor partially rescued the ovulation rate of the two chronic stress models. This study reveals that managing stress and potentially targeting the P2X7 receptor could help improve reproductive health in women experiencing chronic stress, offering a new approach to treating stress-related reproductive issues. 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.