Neointima formation (NF) is a characteristic feature of pathological (i.e. mechano‐injury) and physiological (i.e. vascular development) vascular remodeling. We have demonstrated that chronic stimulation of the prostaglandin E2 (PGE2)‐cAMP‐PKA signal pathway plays a critical role in physiological NF in perinatal ductus arteriosus (DA), a fetal bypass artery between the aorta and pulmonary artery. EPAC, a newly identified effector of cAMP, may play a distinct role from PKA in pathophsiology of NF. Quantitative RT‐PCR and immunoistochemical analyses revealed that the levels of EPAC1 were significantly upregulated in the rat perinatal DA and the mechanically injured artery. 8‐pCPT‐2′‐O‐Me‐cAMP, a cAMP analog selective to EPAC activator promoted smooth muscle cell (SMC) migration in a dose‐dependent manner. Adenovirus‐mediated EPAC1 gene transfer further enhanced 8‐pCPT‐2′‐O‐Me‐cAMP‐induced cell migration. In addition, transfection of siRNAs for EPAC1 significantly inhibited serum‐mediated SMC migration. Actin stress fibers were well‐organized with enhanced focal adhesion and cell shape was widely expanded in the presence of 8‐pCPT‐2′‐O‐Me‐cAMP. Adenovirus‐mediated EPAC1 gene transfer induced prominent NF in the rat DA explants. Thus EPAC promotes SMC migration and thereby pathophysiological NF.