Sphingosine-1-Phosphate and the Leading Edg-1 of Vascular Smooth Muscle Cells
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The migration of vascular smooth muscle cells (VSMCs) from the media to the intima in concert with their subsequent massive proliferation within the intima characterizes restenosis after angioplasty, occlusion of saphenous vein grafts, transplant organ failure, and the progression of atherosclerosis. The identification of molecules and mechanisms that regulate VSMC migration and proliferation is therefore of considerable clinical relevance. A key discovery that led Ross and Glomset1 to propose the “response to injury” hypothesis of atherosclerosis was the release of platelet-derived growth factor (PDGF), a potent chemoattractant and mitogen for VSMC upon platelet activation. Subsequent studies showed that PDGF is also produced by endothelial cells, macrophages, and SMCs themselves. A role for PDGF signaling in migration and proliferation of intima VSMCs and in the pathogenesis of plaque development and restenosis is now well established.2 Studies disrupting the PDGF-B gene or the PDGF-β receptor show that the PDGF-B pathway is required for normal blood vessel formation during embryonic development. Very recently, another class of mediator and another receptor essential for VSMC migration and vascular maturation has been described that involve the lipid sphingosine-1-phosphate (S1P) and its receptor Edg-1.3,4
S1P and the structurally related sister molecule lysophosphatidic acid (LPA) are potent bioactive lipids that have multiple biologic actions on vascular cells and blood cells.5 As is seen with PDGF, S1P is released in large quantities from activated platelets (through a mechanism, which has yet to be described).6 It is also constitutively produced and secreted by other blood cells (mononuclear cells, neutrophils, and red blood cells) albeit in small quantities.6,7 S1P binds with high affinity to the receptor Edg-1, which couples to the Gi protein pathway.8 This receptor, the first of S1P and LPA receptors characterized, was identified as a gene induced during human endothelial …