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

Sphingosine 1-phosphate (S1P) plays important roles in cardiovascular pathophysiology. S1P₁ and/or S1P₃, rather than S1P₂ receptors, seem to be predominantly expressed in vascular endothelial cells, while S1P₂ and/or S1P₃, rather than S1P₁ 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 Ca²⁺ concentration in many cell types, including VSMCs. Activation of S1P₃ seems to play an important role in Ca²⁺ mobilization. S1P induces cyclooxygenase-2 expression in VSMCs via both S1P₂ and S1P₃ receptors. S1P₂ 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 S1P₂ 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.