Role of the Sphingosine 1-Phosphate Receptor EDG-1 in Vascular Smooth Muscle Cell Proliferation and Migration

• Published in: Circulation research 2001-09, Vol.89 (6), p.496-502
• Main Authors: Kluk, Michael J, Hla, Timothy
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Biological and medical sciences; Blood vessels and receptors; Cell Division - drug effects; Cell Movement - drug effects; Cells, Cultured; Culture Media, Serum-Free - pharmacology; Cyclin D1 - drug effects; Cyclin D1 - metabolism; DNA - biosynthesis; DNA - drug effects; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Immediate-Early Proteins - genetics; Immediate-Early Proteins - physiology; Lysophospholipids; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Pertussis Toxin; Protein Isoforms - genetics; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Lysophospholipid; Ribosomal Protein S6 Kinases - drug effects; Ribosomal Protein S6 Kinases - metabolism; RNA, Messenger - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sirolimus - pharmacology; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; Transfection; Vertebrates: cardiovascular system; Virulence Factors, Bordetella - pharmacology
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/hh1801.096338

ABSTRACT—Sphingosine 1-phosphate (S1P), a platelet-derived ligand for the EDG-1 family of G protein–coupled receptors (GPCRs), has recently emerged as a regulator of vascular development. Although S1P has potent effects on endothelial cells and vascular smooth muscle cells (VSMCs), the functions of the specific S1P receptors in the latter cell type are not known. Here we show that pup-intimal VSMCs express higher levels of EDG-1 mRNA than adult-medial VSMCs. Stable transfection of EDG-1 into adult-medial VSMCs enhanced their proliferative response to S1P, concomitant with induction of p70 S6 kinase activity and expression of cyclin D1. Pertussis toxin treatment inhibited S1P-induced p70 S6 kinase activation, cyclin D1 expression and proliferation, suggesting that EDG-1–coupling to the Gi pathway is critical. Furthermore, blocking p70 S6 kinase phosphorylation with rapamycin inhibited cyclin D1 expression and proliferation, suggesting that activation of p70 S6 kinase is critical in EDG-1/Gi–mediated cell proliferation. EDG-1 expression also profoundly enhanced the migratory response of adult-medial VSMCs to S1P. S1P-induced migration of adult-medial VSMCs expressing exogenous EDG-1 required Gi activation but not p70 S6 kinase. These results suggest that enhanced expression of EDG-1 in VSMCs dramatically stimulates both the proliferative and migratory responses to S1P. Since EDG-1 is expressed in the pup-intimal phenotype of VSMCs, S1P signaling via EDG-1 may play a role in vascular diseases in which the proliferation and migration of VSMCs are dysregulated.