Background: After angioplasty, vascular smooth muscle cell (VSMC)s undergo phenotypic and proliferative changes in response to balloon injury. Some studies have demonstrated that neointimal formation after injury is associated with reduced vascular cGMP-dependent Protein Kinase (PKG) in VSMCs. This suggests that PKG occupies a central switching role in the modulation of VSMC phenotype in response to injury. In cancer cells, it is well known that Exisulind exert antiproliferative effects through PKG activation. Here, we examined the effects of Exisulind on neointimal formation after balloon injury and its action mechanism. Methods and results: In WST-1 assay and incorporation of BrdU, Exisulind reduced the viable and proliferative cell numbers in a dose-dependent manner. In cell cycle and apoptosis FACS, Exisulind arrested the cell cycle at G1 phase and showed increased apoptotic VSMCs. In Western blot, Exisulind induced activation of PKG, MEKK and JNK and reduced the level of 棺-catenin. In immunofluorescence method, Exisulind increased calponin expression, one of the markers in contractile form of VSMC, which reduced by treatment of PDGF-BB. Gene transfer of catalytically inactive form of PKG reversed the effects of Exisulind on VSMCs viability and migration. At 2 weeks after injury, Exisulind significantly reduced intima-to-media ratio (vehicle vs Exisulind (n=10/group, 0.89짹0.16, p<0.05). Conversely, gene delivery of catalytically inactive form of PKG reversed the inhibition of intimal hyperplasia by Exisulind. Conclusion: This study demonstrated that Exisulind is potential inhibitors of neointimal formation by activation of PKG and downregulation of 棺-catenin. Our findings suggest a potential use for Exisulind in the prevention of restenosis after angioplasty as DES.