Abstract
IntroductionFailure of trophoblast invasion and remodelling of maternal blood vessels leads to the pregnancy complication pre-eclampsia (PE). In other systems, the sphingolipid, sphingosine-1-phosphate (S1P), controls cell migration therefore this study determined its effect on extravillous trophoblast (EVT) function. MethodsA transwell migration system was used to assess the behaviour of three trophoblast cell lines, Swan-71, SGHPL-4, and JEG3, and primary human trophoblasts in the presence or absence of S1P, S1P pathway inhibitors and 1,25(OH)2D3. QPCR and immunolocalisation were used to demonstrate EVT S1P receptor expression. ResultsEVTs express S1P receptors 1, 2 and 3. S1P inhibited EVT migration. This effect was abolished in the presence of the specific S1PR2 inhibitor, JTE-013 (p < 0.05 versus S1P alone) whereas treatment with the S1R1/3 inhibitor, FTY720, had no effect. In other cell types S1PR2 is regulated by vitamin D; here we found that treatment with 1,25(OH)2D3 for 48 or 72 h reduces S1PR2 (4-fold; <0.05), but not R1 and R3, expression. Moreover, S1P did not inhibit the migration of cells exposed to 1,25(OH)2D3 (p < 0.05). DiscussionThis study demonstrates that although EVT express three S1P receptor isoforms, S1P predominantly signals through S1PR2/Gα12/13 to activate Rho and thereby acts as potent inhibitor of EVT migration. Importantly, expression of S1PR2, and therefore S1P function, can be down-regulated by vitamin D. Our data suggest that vitamin D deficiency, which is known to be associated with PE, may contribute to the impaired trophoblast migration that underlies this condition.
Highlights
Failure of trophoblast invasion and remodelling of maternal blood vessels leads to the pregnancy complication pre-eclampsia (PE)
Extracellular S1P functions through its receptors, S1PR1e5 and in this study we demonstrated the presence of S1PR1-3 on primary extravillous trophoblast (EVT) cells and in our trophoblast models
Previous studies of other cell types have indicated that the effect of S1P on migration and invasion depends on which S1P receptor(s) are activated
Summary
Failure of trophoblast invasion and remodelling of maternal blood vessels leads to the pregnancy complication pre-eclampsia (PE). The sphingolipid, sphingosine-1phosphate (S1P), controls cell migration this study determined its effect on extravillous trophoblast (EVT) function. Discussion: This study demonstrates that EVT express three S1P receptor isoforms, S1P predominantly signals through S1PR2/Ga12/13 to activate Rho and thereby acts as potent inhibitor of EVT migration. Abnormalities in EVT function result in the shallow placental invasion seen in the serious pregnancy disease pre-eclampsia (PE) [2]. A study using metabolomics to profile placental tissue in pregnancies complicated by PE [10] identified deranged sphingolipid metabolism as one of only a handful of pathways altered in this condition
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