T. Kimura et al., Sphingosine 1-phosphate stimulates proliferation and migration of human endothelial cells possibly through the lipid receptors, Edg-1 and Edg-3, BIOCHEM J, 348, 2000, pp. 71-76
Sphingosine 1-phosphate (S1P) stimulates thymidine incorporation (DNA synth
esis), cell growth and cell migration in human aortic endothelial cells (HA
ECs). The extent of the S1P-induced responses are comparable to those stimu
lated by vascular endothelial growth factor, one of the most potent stimula
tors of angiogenesis. These responses to SIP were mimicked by dihydrosphing
osine l-phosphate, an SIP receptor agonist, and inhibited by pertussis toxi
n (PTX), an inactivator of G(i)/G(o)-proteins. SLP also induced activation
of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated pr
otein kinase (p38 MAP kinase). The activation of these enzymes was inhibite
d again by PTX and also by suramin, a non-selective receptor antagonist. SI
P-induced DNA synthesis and ERK activation were inhibited by PD98059, an ER
K kinase inhibitor, but not by SB203580, a p38 MAP kinase inhibitor. In con
trast, cell migration and p38 MAP kinase activation, in response to S1P, we
re inhibited by SB203580 but not by PD98059. In HAECs, high-affinity S1P bi
nding 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 li
nked to signalling pathways.