Sphingosine-1-phosphate inhibition of placental trophoblast differentiation through a Gi-coupled receptor response

Edward D. Johnstone, Colin P. Sibley, Sandra T. Davidge, Bonnie Lowen, and Larry J. Guilbert

Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G2S2

Corresponding Author: larry.guilbert{at}ualberta.ca

The failure of placental trophoblasts to differentiate properly is thought to play an important role in etiology of pregnancy disorders such as pre-eclampsia (PE). We looked at the effects of the bioactive lipid sphingosine-1-phosphate (S1P) on the differentiation of primary human cytotrophoblasts (CT) into syncytiotrophoblasts in culture. We found S1P inhibited CT differentiation measured by chorionic gonadotropin secretion and expression of placental alkaline phosphatase but had no effect on their fusion into multinucleated syncytialized cells. G-protein-linked S1P receptors 1, 2 and 3 were found in CT by reverse transcriptase polymerase chain reaction and receptor 1 by western blot analysis. Disruption of Gi signalling with pertussis toxin reversed the inhibitory effects of S1P. S1P reduced intracellular cAMP and addition of 8-bromo-c-AMP reversed S1P inhibition of hCG secretion. We therefore suggest that S1P inhibits differentiation of CT into syncytiotrophoblasts through Gi-coupled S1P receptor interaction(s) leading to inhibition of adenylate cyclase and reduced production of intracellular cAMP. This is the first reported effect of S1P on placental trophoblast function.

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