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

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. Case-control laboratory study. University research institute and university hospital. A total of 75 women, with and without endometriosis, were included in the study. 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. 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) β1. mRNA expression analysis of S1PR demonstrated a deep dysregulation of S1P signaling in endometriosis, characterized by increased expression of fibrosis markers: S1P1 was transcriptionally more expressed in OMA, and S1P3 and S1P5 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 TGFβ1 was highlighted in vitro. The S1P signaling axis may represent a useful biomarker or innovative pharmacologic target for endometriosis. Los receptores de la Esfingosina 1-fosfato están alterados en endometriosis: Posible implicación en la fibrosis inducida por el factor de crecimiento transformador beta. Estudiar los mecanismos moleculares implicados en la característica de apariencia fibrótica en endometriosis mediante la investigación de si la vía de señalización del esfingolípido Esfingosina 1-fosfato (SP1) bioactivo estaba alterada en las lesiones endometriosicas. Un estudio caso-control de laboratorio. Instituto de investigación universitario y hospital universitario. Un total de 75 mujeres, con y sin endometriosis, fueron incluidas en el estudio. Muestras endometriales fueron obtenidas a partir de mujeres afectadas (n=15 endometrioma [OMA]; n=30 en