Elevated Sphingosine‐1‐Phosphate Influences Cardiac Cushion Development through the S1P3 Receptor

Abstract

Sphingosine‐1‐phosphate (S1P) is a biologically active sphingolipid metabolite that influences numerous cellular events including differentiation, proliferation and migration. S1P acts through its cell surface receptors S1P1‐5, and four of these receptors (S1P1, 2, 3, 4) are expressed in the developing heart. S1P signaling is critical for vascular maturation, however its effects on early cardiac development are not well known. To address this issue, we used in vitro atrioventricular (AV) canal cultures to examine the role of S1P signaling during endothelial to mesenchymal transformation (EMT). Addition of S1P altered cell morphology, inhibited cell migration, and blocked EMT. FTY720 an agonist to S1P1, 3, 4, 5 had similar results as S1P on AV canal cultures. In addition, CAY10444, an inhibitor of S1P3, protected cultures from FTY720 treatment. These results and previous work, showing that a S1P1 specific agonist had no effect on AV canal cultures, identify S1P3 as the mediator of the S1P signal that leads to cell rounding, reduced motility, and inhibition of EMT. Supported by American Heart Association (0756000T).