Objectives: Vascular remodeling after mechano-injury largely depends upon the migration of smooth muscle cells, an initial key step to wound healing. However, the role of the second messenger system, in particular, cAMP signal, in regulating such remodeling remains controversial. Epac has been identified as a new target molecule of cAMP signal, which is independent from PKA. We thus examined whether Epac plays a distinct role from PKA in vascular remodeling. Methods and Results: To examine the role of Epac and PKA in migration, we used primary culture smooth muscle cells from both fetal and adult rat aorta. A cAMP analog selective to PKA, pCPT-cAMP, decreased cell migration while an Epac-selective analog, 8-pCPT-2’-O-Me-cAMP, enhanced migration. Adenovirus-mediated gene transfer of PKA decreased cell migration while that of Epac1 significantly enhanced cell migration. Striking morphological differences were observed between pCPT-cAMP- and 8-pCPT-2’-O-Me-cAMP-treated aortic smooth muscle cells. Furthermore, overexpression of Epac1 enhanced the development of neointimal formation in fetal rat aortic tissues in organ culture. When mouse femoral artery was injured mechanically in vivo, we found that the expression of Epac1 was upregulated in vascular smooth muscle cells while that of PKA was downregulated with the progress of neointimal thickening. Conclusions: Our findings suggest that Epac1, in opposition to PKA, increases vascular smooth muscle cell migration. Epac may thus play an important role in advancing vascular remodeling and restenosis upon vascular injury.