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Sphingosine 1-phosphate suppresses the viability and estradiol secretion of mouse granulosa cells by activating Gα12/13-YAP signaling

Xiaoling Fu^a, Shuangshuang Liang^b,*

 
ABSTRACT:     Polycystic ovary syndrome (PCOS) is a disease with abnormal hormones affecting 6?8% of women in reproductive age. Accumulating evidence supports the critical role of sphingosine 1-phosphate (S1P), a biologically active lipid, in PCOS mechanisms. Downstream of S1P, the G protein-coupled receptor (GPCR) family member S1PRs transduce the signal to the Hippo/yes-associated protein 1 (YAP) signal axis which might be involved in the survival, growth, and death of ovarian granulosa cells (GCs), which let us suppose whether S1P contributes to the development of PCOS by regulating G?12/13-YAP signaling in GCs. This study was designed to examine the action of the S1P/GPCR/YAP signal axis on GCs with a focus on estrogen response of cell viability. The distribution of all S1PRs in mouse ovarian GCs was determined, and it was found that S1PR2 exhibited the strongest expression. In GCs, S1P inhibited YAP phosphorylation at Ser127 and promoted YAP translocation from cytosol to the nucleus. S1P attenuated viability of GCs through activating YAP from G?12/13 under GPCR activation, which was restored by excessive ?estradiol, indicating the role of S1P/GPCR/YAP signal in estrogen response. Furthermore, S1P also activated YAP to suppress the secretion of estrogen from GCs. The findings presented here provide an inviting therapeutic option for PCOS which involves the dysfunction of GCs.

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* Corresponding author, E-mail: lshuang2004@163.com

Received 17 Oct 2022, Accepted 27 Jun 2023