Sphingosine 1-phosphate receptors are dysregulated in endometriosis possible implication in transforming growth factor β-induced fibrosis

Objective: To study the molecular mechanisms involved in the appearance of the fibrotic trait in endometriosis by investigating whether the signaling pathway of the bioactive sphingolipid sphingosine 1-phosphate (S1P) was altered in endometriotic lesions. Design: Case-control laboratory study. Setting: University research institute and university hospital. Patient(s): A total of 75 women, with and without endometriosis, were included in the study. Interventions(s): Endometrial samples were obtained from women affected (n = 15 endometrioma [OMA]; n = 30 deep infiltrating endometriosis [DIE]) and not (n = 30) by endometriosis by means of laparoscopic surgery, followed by clinical and imaging investigation and checking for the expression of fibrosis markers and genes implicated in S1P metabolism and signaling by means of real-time polymerase chain reaction. Main Outcome Measure(s): The role of the S1P signaling axis in endometriosis-associated fibrosis was studied in vitro, where RNA interference approaches were used to investigate if S1P synthesis by sphingosine kinases (SKs) and specific S1P receptors (S1PRs) are implicated in the profibrotic effect of the cytokine transforming growth factor (TGF) beta 1. Result(s): mRNA expression analysis of S1PR demonstrated a deep dysregulation of S1P signaling in endometriosis, characterized by increased expression of fibrosis markers: S1P(1) was transcriptionally more expressed in OMA, and S1P(3) and S1P(5) mRNA levels were significantly augmented in both OMA and DIE. SK1 and its activating protein calcium-and integrin-binding protein 1 (CIB1) were significantly up-regulated in OMA and DIE. A crucial role for the SK/S1PR axis in the profibrotic effect elicited by TGF beta 1 was highlighted in vitro. Conclusion(s): The S1P signaling axis may represent a useful biomarker or innovative pharmacologic target for endometriosis. ((C) 2020 by American Society for Reproductive Medicine.)

Automated summary

This study investigates the molecular mechanisms involved in the fibrotic trait of endometriosis through examining the alterations of the S1P signaling pathway. The results show a deep dysregulation of S1P signaling in endometriosis, with S1P synthesis enzymes and receptors playing a crucial role in promoting fibrosis.