Cellular function and signaling pathways of vascular smooth muscle cells modulated by sphingosine 1-phosphate

Abstract Sphingosine 1-phosphate (S1P) plays important roles in cardiovascular pathophysiology. S1P 1 and/or S1P 3 , rather than S1P 2 receptors, seem to be predominantly expressed in vascular endothelial cells, while S1P 2 and/or S1P 3 , rather than S1P 1 receptors, seem to be predominantly expressed in vascular smooth muscle cells (VSMCs). S1P has multiple actions, such as proliferation, inhibition or stimulation of migration, and vasoconstriction or release of vasoactive mediators. S1P induces an increase of the intracellular Ca 2+ concentration in many cell types, including VSMCs. Activation of S1P 3 seems to play an important role in Ca 2+ mobilization. S1P induces cyclooxygenase-2 expression in VSMCs via both S1P 2 and S1P 3 receptors. S1P 2 receptor activation in VSMCs inhibits inducible nitric oxide synthase (iNOS) expression. At the local site of vascular injury, vasoactive mediators such as prostaglandins and NO produced by VSMCs are considered primarily as a defensive and compensatory mechanism for the lack of endothelial function to prevent further pathology. Therefore, selective S1P 2 receptor antagonists may have the potential to be therapeutic agents, in view of their antagonism of iNOS inhibition by S1P. Further progress in studies of the precise mechanisms of S1P may provide useful knowledge for the development of new S1P-related drugs for the treatment of cardiovascular diseases.