Sphingosine 1-phosphate signaling in uterine fibroids: implication in activin A pro-fibrotic effect

Objective: To explore the link between sphingosine 1-phosphate (S1P) signaling and leiomyoma and the possible S1P cross-talk with the fibrotic effect of activin A. Design: Case-control laboratory study. Setting: University institute and university hospital. Patient(s): Patients with uterine fibroids (n = 26). Interventions(s): Tissue specimens of leiomyoma and normal myometrium were obtained from patients undergoing myomectomy or total hysterectomy. Main Outcome Measure(s): Expression of mRNA levels of the enzyme involved in S1P metabolism, S1P receptors, and S1P transporter Spns2 was evaluated in matched leiomyoma/myometrium specimens and cell populations. The effects of inhibition of S1P metabolism and signaling was evaluated on activin A–induced fibrotic action in leiomyoma cell lines. Result(s): The expression of the enzymes responsible for S1P formation, sphingosine kinase (SK) 1 and 2, and S1P2, S1P3, and S1P5 receptors was significantly augmented in leiomyomas compared with adjacent myometrium. In leiomyoma cells, but not in myometrial cells, activin A increased mRNA expression levels of SK1, SK2, and S1P2. The profibrotic action of activin A was abolished when SK1/2 were inhibited or S1P2/3 were blocked. Finally, S1P augmented by itself mRNA levels of fibrotic markers (fibronectin, collagen 1A1) and activin A in leiomyomas but not in myometrial cells. Conclusion(s): This study shows that S1P signaling is dysregulated in uterine fibroids and involved in activin A–induced fibrosis, opening new perspectives for uterine fibroid treatment.