Cigarette smoking affects all phases of atherosclerosis from endothelial dysfunction to acute occlusive clinical events. We explored activation by exposure to tobacco smoke of two genes, -catenin and COX-2, that play key roles in inflammation and vascular remodeling events. Using both in vivo and in vitro smoke exposure, we determined that tobacco smoke (TS) induced nuclear -catenin accumulation and COX-2 expression and activity and moreover interacted with IL-1 to enhance these effects. Exposure of cardiac endothelial cells to tobacco smoke plus IL-1 (TS/IL-1) enhanced permeability of endothelial monolayers and disrupted membrane VE-cadherin/-catenin complexes, decreased -catenin phosphorylation, and increased phosphorylation of GSK-3, Akt, and EGFR. Transfection of endothelial cells with -catenin-directed small interferring RNA (siRNA) suppressed TS/IL-1-mediated effects on COX-2 modulation. Inhibitors of EGFR and phosphatidylinositol-3-kinase also abolished both the TS/IL-1-mediated modulation of the Akt/GSK-3/-catenin pathway and enhancement of COX-2 expression. Moreover, increased levels of Akt and GSK-3 phosphorylation, nuclear -catenin accumulation, COX-2 expression, and IL-1 were observed in cardiovascular tissue of ApoE^-/- mice exposed to cigarette smoke daily for 2 wk. Our results suggest a novel mechanism by which cigarette smoking can induce proinflammatory and proatherosclerotic effects in vascular tissue.--Barbieri, S. S., Weksler, B. B. Tobacco smoke cooperates with interleukin-1 to alter -catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase-2 expression in vitro and in vivo.