ABSTRACT: Very little is known about how lipid signaling regulates intima hyperplasia after vascular injury. Herein, we report that deletion and pharmacological inhibition of phospholipase D (PLD)2, which generates the signaling lipid phosphatidic acid (PA), reduced neointimal formation in the mouse carotid artery ligation model. PLD2 deficiency inhibits migration of vascular smooth muscle cells (VSMCs) into the intima in mice as well as migration and formation of membrane ruffles in primary VSMCs. PA specifically binds to the IQ motif-containing guanosine triphosphatase-activating protein 1 (IQGAP1) scaffold protein. The binding between PA and IQGAP is required for the plasma membrane recruitment of IQGAP1. Similar to PLD2 inhibition, knockdown of IQGAP1 blocks ruffle formation and migration in VSMCs, which are rescued by expression of the exogenous IQGAP1 but not the PA binding-deficient mutant. These data reveal that the PLD2-PA-IQGAP1 pathway plays an important role in VSMC migration and injury-induced vascular remodeling, and implicate PLD2 as a candidate target for therapeutic interventions.-Wang, Z., Cai, M., Tay, L. W. R., Zhang, F., Wu, P., Huynh, A., Cao, X., Di Paolo, G., Peng, J., Milewicz, D. M., Du, G. Phosphatidic acid generated by PLD2 promotes the plasma membrane recruitment of IQGAP1 and neointima formation.
