Sphingosine 1-Phosphate Receptor 2 Negatively Regulates Neointimal Formation in Mouse Arteries

Abstract

Neointimal lesion formation was induced in sphingosine 1-phosphate (S1P) receptor 2 (S1P 2 )-null and wild-type mice by ligation of the left carotid artery. After 28 days, large neointimal lesions developed in S1P 2 -null but not in wild-type arteries. This was accompanied with a significant increase in both medial and intimal smooth muscle cell (SMC) replication between days 4 to 28, with only minimal replication in wild-type arteries. S1P 2 -null SMCs showed a significant increase in migration when stimulated with S1P alone and together with platelet-derived growth factor, whereas both wild-type and null SMCs migrated equally well to platelet-derived growth factor. S1P increased Rho activation in wild-type but not in S1P 2 -null SMCs, and inhibition of Rho activity promoted S1P-induced SMC migration. Plasma S1P levels were similar and did not change after surgery. These results suggest that activation of S1P 2 normally acts to suppress SMC growth in arteries and that S1P is a regulator of neointimal development.