Sphingosine-1-Phosphate-Induced Inflammation Involves Receptor Tyrosine Kinase Transactivation in Vascular Cells

Abstract

Abstract-Sphingosine-1-phosphate (S1P), a multifunctional phospholipid, regulates vascular cell function. Whether S1P influences vascular inflammatory responses, particularly in hypertension, is unclear. We tested the hypothesis that S1P is a proinflammatory mediator signaling through receptor tyrosine kinase transactivation and that responses are amplified in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats (SHRSPs), a model in which we demonstrated Edg1 (S1P1 receptor) to be a candidate gene for salt-sensitive hypertension. Vascular smooth muscle cell from Wistar-Kyoto rats and SHRSPs were studied. S1P receptor subtypes, S1P1 and S1P2, were similarly expressed in Wistar-Kyoto rats and SHRSPs. S1P induced phosphorylation of epidermal growth factor receptor and platelet-derived growth factor and activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, with amplified effects in SHRSPs versus Wistar-Kyoto rats. Inhibition of epidermal growth factor receptor and plateletderived growth factor (with AG1478 and AG1296, respectively) abolished S1P-induced phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase in Wistar-Kyoto rats with variable effects in SHRSPs. Vascular smooth muscle cell inflammation was evaluated by expression of adhesion molecules and functional responses assessed by monocyte adhesion. S1P stimulated expression of intercellular adhesion molecule 1 and vascular cell adhesion protein 1 and promoted monocyte adhesion, particularly in SHRSP cells. S1P-mediated inflammation was blunted by AG1478 and AG1296 in SHRSP cells. VPC23019, a S1P1 receptor antagonist, inhibited S1P-induced mitogen-activated protein kinase phosphorylation, intercellular adhesion molecule 1 and vascular cell adhesion protein 1 expression, and monocyte adhesion.Our data indicate that molecular processes underlying vascular inflammation and cell adhesion in SHRSPs involve S1P/S1P1 receptors and phosphorylation of receptor tyrosine kinases. We identify a novel pathway linking S1P/S1P1 receptors to specific proinflammatory signaling pathways through epidermal growth factor receptor and platelet-derived growth factor transactivation, a process that is upregulated in SHRSPs. Such molecular events may contribute to vascular inflammation in hypertension. (Hypertension. 2011;57:809-818.) • Online Data Supplement Key Words: sphingosine-1-phosphate Ⅲ SHRSP Ⅲ EGFR Ⅲ PDGFR Ⅲ inflammation S phingosine 1-phosphate (S1P), an important structural entity of biological membranes, is also a bioactive lipid mediator involved in cell proliferation, survival, migration, and inflammation in various cell types, including vascular smooth muscle cells (VSMCs). 1-3 S1P serves as a ligand for a subset of G protein-coupled receptors, of which 5 mammalian S1P receptors (S1P1 through S1P5) have been identified. VSMCs, in culture, express S1P1, S1P2, and S1P3 receptors. 4 -8 The downstream targets of S1P signaling include adenylate cyclase, Ras, mitogen-activated protein kinase (MA...

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“…7 In this study, we found that both SS plasma and S1P directly enhanced monocyte-endothelial cell adhesion ( Figure 5A-B). Although S1P has been shown to alter monocyte morphology and motility through the activation of r-kinase 46 and receptor tyrosine kinases, 47 more comprehensive studies need to be performed to elucidate the receptor-specific signaling mechanism behind S1P-mediated monocyte adhesion.…”

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