on June 5, 2008
Published online before print June 5, 2008, doi: 10.1161/ATVBAHA.107.159392
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Submitted on November 20, 2007
Accepted on May 22, 2008
Sphingosine-1-Phosphate Receptor Subtypes Differentially Regulate Smooth Muscle Cell Phenotype
Brian R. Wamhoff *;
From the Department of Medicine, Cardiovascular Division (B.R.W.), the Department of Pharmacology (K.R.L.), the Department of Chemistry (T.L.M.), the Department of Molecular Physiology and Biological Physics (B.R.W., G.K.O.), and the Robert M. Berne Cardiovascular Research Center (B.R.W., G.K.O.), University of Virginia, Charlottesville.
* To whom correspondence should be addressed. E-mail: Wamhoff{at}virginia.edu.
Objective—The role of S1P receptors in acute vascular injury and smooth muscle cell (SMC) phenotypic modulation is not completely resolved.
Methods and Results—S1P receptor antagonists were used to test the hypothesis that specific S1P receptor subtypes differentially regulate SMC phenotypic modulation. In response to acute balloon injury of the rat carotid artery, S1P1/S1P3 receptor mRNA levels were transiently increased at 48 hours whereas S1P2 receptor expression was decreased. S1P2 expression was reinduced and increased at 7 to 10 days postinjury. Daily intraperitoneal injection of the S1P1/S1P3 antagonist VPC44116 decreased neointimal hyperplasia by 
50%. In vitro, pharmacological inhibition of S1P1/S1P3 receptors with VPC25239 attenuated S1P-induced proliferation of rat aortic SMCs. Conversely, inhibition of S1P2 with JTE013 potentiated S1P-induced proliferation. Inhibition of S1P1/S1P3 resulted in S1P-induced activation of the SMC differentiation marker genes SM
-actin and SMMHC, whereas inhibition of S1P2 attenuated this response. S1P2-dependent activation of SM-actin and SMMHC was shown to be mediated by L-type voltage-gated Ca2+ channels and subsequent RhoA/Rho kinase–dependent SRF enrichment of CArG box promoter regions.
Conclusion—Results provide evidence that S1P1/S1P3 receptors promote, whereas S1P2 receptors antagonize, SMC proliferation and phenotypic modulation in vitro in response to S1P, or in vivo after vascular injury.
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