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

Abstract

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 S1P were mimicked by dihydrosphingosine 1-phosphate, an S1P receptor agonist, and inhibited by pertussis toxin (PTX), an inactivator of G i \G o -proteins. S1P 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. S1P-induced DNA synthesis and ERK activation were inhibited

Sphingosine 1-phosphate antagonizes human neutrophil apoptosis via p38 mitogen-activated protein kinase

“…Furthermore, we observed that the anti-apoptotic effect of SPP is mediated by a PTX-sensitive G protein, suggesting the involvement of a G protein-coupled receptor. Certain members of the Edg family of G protein-coupled receptors (which includes Edg-1, -3 -5, -6 and -8) have been shown to specifically bind SPP [32,34,35], and mRNA for Edg-1 to -6 has been detected in human neutrophils [33]. Here we complement the latter findings by demonstrating that Edg receptors are also expressed at the protein level in human neutrophils.…”

“…In accordance with these findings, mRNA for SPP-binding Edg receptors has been detected in human neutrophils [33]. In several cell types, SPP has been shown to affect ERK and p38 MAPK activities by a mechanism that is sensitive to pertussis toxin and therefore most probably occurs through a G protein-coupled receptor [32][33][34][35]. However, in Edg receptor-transfected CHO cells, the SPP-induced effects on both p38 MAPK and JNK activities were shown to be mediated by a pertussis toxin-insensitive signalling pathway [36].…”

“…We also noted that the p38 MAPK inhibitor SB203580 counteracted the SPP-induced reductions of caspase-3 activity and nuclear condensation. These results Research Article 783 suggest that the survival mechanism induced by SPP in neutrophils is, at least in part, mediated by a p38 MAPK signalling pathway that is different from the mechanisms proposed for a variety of other cell systems, which are believed to involve ERK [27,34]. The demonstration that SPP can increase the activity of myosin light-chain phosphatase [51], and the observation that activation of the SH2 domain-containing tyrosine phosphatase-1 promotes cell death in myeloid cells [52] suggest that the presently observed SPP-induced increase in p38 MAPK activity could be mediated via inhibition of a phosphatase rather than promoting a kinase-induced phosphorylation of p38 MAPK.…”

“…Here we complement the latter findings by demonstrating that Edg receptors are also expressed at the protein level in human neutrophils. In addition, the receptors for Edg-1 and -3 have been reported to interact with the PTX-sensitive G i /G o proteins in endothelial and smooth muscle cells [34,35]. These findings could imply that all ligands such as fMLP, which bind to a receptor coupled to a PTX-sensitive G protein, should be able to protect neutrophils from apoptosis.…”

Angiogenesis and signal transduction in endothelial cells

“…This response is blocked by pertussis toxin. S1P induces Ras activation [55] and ERK and p38 MAPK phosphorylation, although endothelial proliferation is blocked only by ERK-MAPK inhibitors [56].…”