Sphingosine 1-phosphate stimulates proliferation and migration of human endothelial cells possibly through the lipid receptors, Edg-1 and Edg-3

Sphingosine 1-phosphate (S1P) stimulates thymidine incorporation (DNA synthesis), cell growth and cell migration in human aortic endothelial cells (HAECs). The extent of the S1P-induced responses are comparable to those stimulated by vascular endothelial growth factor, one of the most potent stimulators of angiogenesis. These responses to SIP were mimicked by dihydrosphingosine l-phosphate, an SIP receptor agonist, and inhibited by pertussis toxin (PTX), an inactivator of G(i)/G(o)-proteins. SLP also induced activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAP kinase). The activation of these enzymes was inhibited again by PTX and also by suramin, a non-selective receptor antagonist. SIP-induced DNA synthesis and ERK activation were inhibited by PD98059, an ERK kinase inhibitor, but not by SB203580, a p38 MAP kinase inhibitor. In contrast, cell migration and p38 MAP kinase activation, in response to S1P, were inhibited by SB203580 but not by PD98059. In HAECs, high-affinity S1P binding activity and expression of Edg-1 and Edg-3 mRNA were detected. These results suggest that SIP might be a novel angiogenesis factor and that the lipid-induced proliferation and migration of endothelial cells are possibly mediated through cell-surface S1P receptors, Edg-1 and Edg-3, which are linked to signalling pathways.