Exogenous sphingosine 1-phosphate and sphingosine kinase activated by endothelin-1 induced myometrial contraction through differential mechanisms

Abstract

Sphingosine 1-phosphate (S1P), a bioactive sphingolipid involved in diverse biological processes, is generated by sphingosine kinase (SphK) and acts via intracellular and/or extracellular mechanisms. We used biochemical, pharmacological, and physiological approaches to investigate in rat myometrium the contractile effect of exogenous S1P and the possible contribution of SphK in endothelin-1 (ET-1)-mediated contraction. S1P stimulated uterine contractility (EC(50) = 1 microM and maximal response = 5 microM) by a pertussis toxin-insensitive and a phospholipse C (PLC)-independent pathway. Phosphorylated FTY720, which interacts with all S1P receptors, except S1P(2) receptors, failed to mimic S1P contractile response, indicating that the effects of S1P involved S1P(2) receptors that are expressed in myometrium. Contraction mediated by S1P and ET-1 required extracellular calcium and Rho kinase activation. Inhibition of SphK reduced ET-1-mediated contraction. ET-1, via ET(A) receptors coupled to pertussis toxin-insensitive G proteins, stimulated SphK1 activity and induced its translocation to the membranes. Myometrial contraction triggered by ET-1 is consecutive to the sequential activation of PLC, protein kinase C, SphK1 and Rho kinase. Prolonged exposure of the myometrium to S1P downregulated S1P(2) receptors and abolished the contraction induced by exogenous S1P. However, in these conditions, the tension triggered by ET-1 was not reduced, indicating that SphK activated by ET-1 contributed to its contractile effect via a S1P(2) receptor-independent process. Our findings demonstrated that exogenous S1P and SphK activity regulated myometrial contraction and may be of physiological relevance in the regulation of uterine motility during gestation and parturition.

Hormonal signaling and signal pathway crosstalk in the control of myometrial calcium dynamics

“…Other signaling pathways-Another potentially important signaling pathway in myometrium involves sphingosine kinase-1, which produces sphingosine-1-P. Endothelin-1 affects Rho-/Rho kinase-dependent pathways via activation of this pathway [30].…”

Signaling Pathways Involved in Sphingosine Kinase Activation and Sphingosine-1-Phosphate Release in Rat Myometrium in Late Pregnancy: Role in the Induction of Cyclooxygenase 2

“…Smooth muscle contractility is also regulated by sphingosine-1-phosphate (S1P) (6). We recently reported that in nonpregnant rat myometrium, contraction is stimulated by exogenous S1P or by ET-1-induced endogenous S1P production, through sphingosine kinase 1 (SphK1) activation (7).…”

“…S1P interacts with five specific S1P receptors belonging to the G proteincoupled receptors (GPCR) family (8,9). S1P triggers several different signaling processes involved in smooth muscle contraction (6,7) as well as numerous target cell processes including cell proliferation, cell growth, migration, adhesion, generation of certain molecules, morphogenesis, cell survival, and apoptosis (8 -10). Additionally, SphK activation can exert intracellular effects, independently from the interaction between S1P and S1P membrane receptors (11).…”

Role of lysophosphatidic acid in the regulation of uterine leiomyoma cell proliferation by phospholipase D and autotaxin

“…This lipid mediator acts via membrane receptors and regulates the ERK 1/2 signaling pathway and many physiological and pathological processes, including proliferation, survival, and contraction (42,43). Recent data from our group demonstrated that ET-1 activates SphK1, which contributes to ET-1-mediated myometrial contraction (44). Furthermore, we recently reported that in ELT3 cells, SphK1 and S1P exerted an antiapoptotic effect (4) and that exogenous S1P stimulated DNA synthesis (unpublished results).…”