Sphingosine-1-phosphate-induced oxygen free radical generation in smooth muscle cell migration requires Gα12/13 protein-mediated phospholipase C activation

Activation of vascular smooth muscle cells by growth factors leads to cell proliferation and migration, which are integral features of the healing response in a vessel that leads to the development of intimal hyperplasia after bypass grafting, angioplasty, and stenting. Sphingosine-1-phosphate (S-1-P) is a common phospholipid, released from activated platelets at sites of vessel injury. It is a G-protein-coupled receptor agonist that induces smooth muscle cell migration, a key event in the development of intimal hyperplasia. Mechanisms of cell migration are not well defined, and understanding the mechanisms of signal transduction is important in defining potential targets for therapeutic intervention. The present study shows that S-1-P induces oxygen free radical generation through a Gα12/13, PLC-β-mediated mechanism that facilitates smooth muscle cell migration. Targeting choke points in cell signaling, such as membrane G-proteins, is an attractive molecular target in developing therapeutic strategies to moderate restenosis.