P2Y12 Promotes Migration of Vascular Smooth Muscle Cells Through Cofilin Dephosphorylation During Atherogenesis

Objective-P2Y(12) is a well-recognized receptor expressed on platelets and the target of thienopyridine-type antiplatelet drugs. However, recent evidence suggests that P2Y(12) expressed in vessel wall plays a role in atherogenesis, but the mechanisms remain elusive. In this study, we examined the molecular mechanisms of how vessel wall P2Y(12) mediates vascular smooth muscle cells (VSMCs) migration and promotes the progression of atherosclerosis. Approach and Results-Using a high-fat diet-fed apolipoprotein E-deficient mice model, we found that the expression of P2Y(12) in VSMCs increased in a time-dependent manner and had a linear relationship with the plaque area. Moreover, administration of P2Y(12) receptor antagonist for 12 weeks caused significant reduction in atheroma and decreased the abundance of VSMCs in plaque. In cultured VSMCs, we found that activation of P2Y(12) receptor inhibited cAMP/protein kinase A signaling pathway, which induced cofilin dephosphorylation and filamentous actin disassembly, thereby enhancing VSMCs motility and migration. In addition, the number of P2Y(12)-positive VSMCs was decreased in the carotid artery plaque from patients receiving clopidogrel. Conclusions-Vessel wall P2Y(12) receptor, which promotes VSMCs migration through cofilin dephosphorylation, plays a critical role in the development of atherosclerotic lesion and may be used as a therapeutic target for atherosclerosis.