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During the last four decades, there has been a significant improvement in the management of coronary artery disease (CAD). These improvements have been achieved through the following advances: use of angioplasty with a stent; and, the development of drug eluting stents (DES). However, the occurrence of in-stent stenosis (ISS) following these procedures results in failure rates of 5-25% depending on the procedure. DES inhibit the proliferation and migration of vascular smooth muscle cells (VSMCs), the main culprit of restenosis and ISS. Fully functional endothelial cells inhibit potential side effects of angioplasty such as thrombus formation and VSMC proliferation and migration. Many studies have suggested that damage to the EC layer and inflammation are important factors that underlie ISS. Inflating the balloon and deploying the stent injures the vessel wall and induces an acute inflammatory response. Thus, anti-inflammatory agents might offer a novel approach for overcoming ISS. Previous studies in our laboratory have shown that non-steroidal anti- inflammatory drugs (NSAIDs) inhibit the proliferation ofVSMCs when used in non-toxic concentrations. In this project, we have investigated the effects of specific NSAIDs on EC proliferation and migration as well as on VSMC migration and phenotype and we try to address the possible mechanisms of actions involved. Our in vitro data indicate that the concentrations of ibuprofen required to inhibit EC migration are higher than those required to inhibit VSMC migration. The effects of aspirin and ibuprofen on proliferation and migration ofVSMCs may be partially mediated via PPARy through the regulation of integrin expressions, as the pretreatment with synthetic antagonist for PP ARy (GW9662 (1 ~M)), or natural antagonist for PPARy (PGF2a(100nM)) partially rescue the inhibitory effects of aspirin and ibuprofen; whilst, COX may mediate the effects of ibuprofen on VSMC proliferation and migration, but not of aspirin, as the exogenous PGF2a (10nM) could rescue the inhibitory effect of ibuprofen. Aspirin and ibuprofen switch VSMC phenotype from a synthetic (pathological) one into a contractile (healthy) phenotype. An IV ibuprofen drug-eluting stent may provide a novel therapeutic strategy for inhibiting an inflammatory response that promotes VSMC differentiation and leads to inhibition of proliferation and migration ofVSMCs without limiting healing of the EC layer.