Abstract 1159: Pharmacological Inhibition of the Sphingosine-1-phosphate Receptors Type 1 and Type 3 with VPC44116 Prevents Neointimal Hyperplasia in the Rat Carotid Artery Injury Model.
Introduction: Sphingosine-1-phosphate (S1P) is a phospholipid that is released by platelets during inflammation and mediates diverse vascular functions including vasculogenesis and vasoconstriction by specific S1P G-protein coupled receptors. Although S1P and S1P receptors have been proposed to play a role in vascular disease, there is no definitive evidence for this. In response to acute vascular injury, e.g. balloon angioplasty, vascular smooth muscle cells undergo phenotypic modulation, suppressing genes that define the contractile/quiescent phenotype and inducing genes required for proliferation and migration that leads to neointimal hyperplasia. SMCs express S1P type 1, 2 and 3 receptors in culture and in vivo.
Methods: Using S1P analogs that have activity as receptor antagonists at one or more S1P receptors, we tested the hypothesis that specific S1P receptor subtypes regulate smooth muscle proliferation in vitro and in vivo using the rat carotid artery balloon injury model.
Results: Pharmacological inhibition of S1P1 and S1P3 receptors with the selective S1P1/S1P3 antagonist VPC25239 attenuated S1P-induced proliferation of rat aortic SMCs in vitro. Conversely, inhibition of the S1P2 receptor with JTE013 potentiated S1P-induced proliferation. These results suggest that the S1P1 and S1P3 receptors mediate S1P-induced smooth muscle proliferation, whereas activation of the S1P2 receptor may attenuate this response. In response to acute balloon injury of the rat carotid artery, S1P1 and S1P3 receptor mRNA levels were transiently increased 36-fold and 5-fold, respectively (P < 0.05), during the first 48 hrs whereas S1P2 receptor expression was decreased by 90% (P < 0.05). To test the functional roles of the S1P1/S1P3 receptors in neointimal hyperplasia, daily intraperitoneal injection of the S1P1/S1P3 antagonist VPC44116 [10 mg/kg] was performed following acute balloon injury. VPC44116 treatment decreased neointimal hyperplasia by ~50% (P = 0.025) 14 days after injury.
Conclusion: These results show that S1P1 and S1P3 receptors mediate S1P-induced smooth muscle proliferation and for the first time provide evidence that the S1P signaling axis plays a critical role in neointimal hyperplasia in response to acute vascular injury in vivo.