Role of Sphingosine ‐1‐Phosphate on Expression of MAPK and Akt Signaling Pathways in Hypoxic Human Extravillous Trophoblasts

Abstract

Preeclampsia (PE), is a serious pregnancy disorder characterized by placental ischemia, hypertension, and proteinuria. A successful pregnancy requires the migration and invasion of extravillous trophoblasts (EVTs), from the villous tips of the placenta into the maternal decidua and subsequently the spiral arteries. Failure of EVTs to adequately migrate and invade into the spiral arteries leads to insufficient blood flow to the developing placenta commonly found in PE. Sphingosine‐1‐phosphate (S1P) functions as a key regulator of cellular homeostasis in angiogenesis, inflammation, and endothelium permeability. S1P acts on its receptor to control cell migration through the PI3‐Akt and p38 MAPK signaling pathways. We have previously reported that expression of placenta ceramidase, sphingosine kinases 1, and sphingosine kinases 2 were altered in reduced uterine perfusion (RUP) mouse model. In the present study, we tested the hypothesis that serine 473 phosphorylated Akt (pAkt) and phosphorylated p38 MAPK expressions are decreased in hypoxic condition and treatment with S1PR 1 agonist and antagonist alter these expression levels.MethodsThe human extravillous trophoblasts (EVTs) cell line SGHPL‐4 was cultured in either normoxia 21% oxygen or hypoxia 2% oxygen conditions for 24 hours. The cultures were treated for one hour with vehicle control or with S1PR1 receptor agonists (SEW2871, 1uM) or S1PR antagonist (W146, 18 nM).ResultsBoth pAkt and p38 MAPK were significantly decreased in hypoxia EVTs compared to normoxia EVTs (p38 MAPK: 50% and pAkt: 25% decrease). SEW2871 increased p38 MAPK in hypoxia EVTs to a level similar to normaxia EVTs. Inhibition of S1PR1 by W146 decreased p38 MAPK in both hypoxia and normoxia. SEW2871 normalized the differences of pAkt expression between normoxia and hypoxia EVTs. While W146 did not change the pAkt in normoxia, it significantly increased pAkt in hypoxia EVTs cells. This data suggests that activation of S1P receptor type 1 increases the expression of angiogenic pMAPK in hypoxic SGHPL‐4 trophoblast cells.Support or Funding InformationDr. Intapad was supported by funding from the AHA 16SDG27770041, ASN Kidney Research Career Development grant, and Start‐up funds from Tulane University.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.