The sphingosine-1-phosphate pathway is differentially activated in human gestational tissues

Abstract Background Dysregulated myometrial contractility contributes to obstetric complications. Sphingosine-1-phosphate (S1P), a bioactive lipid, modulates inflammation and smooth muscle contractility, including uterine contractility. However, its metabolic dynamics during pregnancy are poorly characterized. This study profiled S1P metabolic enzymes and receptors, and quantified sphingolipid metabolites in human gestational tissues across pregnancy. Methods Myometrium, decidua parietalis, and chorioamnion were collected from women undergoing cesarean sections at term (≥37 weeks’ gestation) without labor (TNL, n=8), term with labor (TL, n=5), and preterm (<37 weeks’ gestation) without labor (PTNL, n=6). Messenger RNA (mRNA) expression of S1P metabolic enzymes and receptors was assessed using quantitative polymerase chain reaction, while sphingolipids were quantified using targeted liquid chromatography-tandem mass spectrometry. Results S1P metabolic enzymes and receptors were differentially expressed across gestational tissues. At TNL, sphingosine kinase1 (SPHK1) expression was higher in the decidua parietalis than in the chorioamnion and myometrium. The myometrium exhibited the highest mRNA expression of S1P receptors (S1PR1–4) compared to the decidua and chorioamnion. At term, S1P was more abundant in the myometrium than in the decidua parietalis and chorioamnion. Both SPHK1 and S1P were higher in TL than in TNL myometrium. S1P levels were higher in the myometrium at TNL than at PTNL, with no significant differences in the decidua or chorioamnion. Overall, sphingolipid metabolism was highest in the decidua and myometrium and lowest in the chorioamnion at term. Conclusion These findings reveal tissue-specific regulation of S1P metabolism and signaling in human gestational tissues, suggesting S1P's therapeutic role to modulate myometrial contractility.