Abstract 13023: Sphingosine-1-phosphate Receptor 1 (S1PR1) Promotes Neointimal Formation after Vascular Injury in Mice
Background- Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid mediator that mediates diverse cellular responses including cell proliferation, survival, and migration. S1P acts through 5 members of S1P-specific G-protein coupled receptors (S1PR1-S1PR5). S1PR1 was shown to be essential for vascular maturation during embryonic development and vascular proliferative lesion formation. Recently, it has been reported that expression of S1PR1 was elevated in tumor cells and this elevation contributed to interleukin-6 (IL-6) gene upregulation, thereby accelerating tumor growth and metastasis. Vascular inflammation and smooth muscle proliferation contribute to vascular remodeling and obstructive vasculopathies such as atherosclerosis and restenosis following angioplasty. However, pathophysiological roles of S1P and S1PR1 in atherosclerosis are not known. Here we examined whether S1P could be involved in the development of neointima formation.
Methods and Results- We generated mice that overexpressed S1PR1 (Tg-S1PR1) under the control of α-smooth muscle actin promoter. Tg-S1PR1 and nTg mice were subjected to carotid artery ligation. After 4 weeks following this intervention, intimal hyperplasia was assessed in each group. Intima/Media ratio was significantly higher in Tg-S1PR1 mice compared with nTg mice (0.76 ± 0.16 vs. 0.35 ± 0.05, P<0.01), and neointima area was significantly increased in Tg-S1PR1 mice (0.023 ± 0.006 vs. 0.0090 ± 0.001 mm2, P<0.01). Proliferative cells in the neointima were identified by immunohistochemical staining with Ki-67 monoclonal antibody. Ki-67-positive proliferating cells in the neointima were also increased in Tg-S1PR1 mice compared with nTg mice (Ki-67 positive cells 4.02 ± 0.87 vs. 2.20 ± 0.32%, P<0.05). Furthermore, vascular smooth muscle cells from Tg-S1PR1 mice showed a significant increase in IL-6 concentrations of conditional media compared with those of nTg mice after S1P stimulation.
Conclusions- Overexpression of S1PR1 promotes neointimal formation after vascular injury due to proliferation and IL-6 productions in vascular smooth muscle cells. Inhibition of S1PR1 might be a therapeutic target for preventing arteriosclerosis and arterial restenosis after angioplasty.
- © 2012 by American Heart Association, Inc.