Circulation Research. 2001
Published online before print August 30, 2001, doi: 10.1161/hh1801.096338
Published online before print August 30, 2001, doi: 10.1161/hh1801.096338
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Role of the Sphingosine 1-Phosphate Receptor EDG-1 in Vascular Smooth Muscle Cell Proliferation and Migration
From the Center for Vascular Biology, Department of Physiology, University of Connecticut Health Center, Farmington, Conn.
Correspondence to Dr Timothy Hla, Center for Vascular Biology, Department of Physiology, MC3501, University of Connecticut School of Medicine, 263 Farmington Ave, Farmington, CT 06030. E-mail hla{at}sun.uchc.edu
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.
Key Words: vascular smooth muscle cells • sphingosine 1-phosphate • proliferation • migration
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