Model for the role of Epac/Rap in endothelial barrier function. An en face schematic of 2 endothelial cells is illustrated. cAMP activates Epac, resulting in Rap activation at junctions. This induces reorganization of cortical actin and subsequent redistribution of VE-cadherin and other AJ and TJ molecules, to cell-cell contacts, enhancing macromolecular barrier function. AF-6, an effector of Rap, may direct Epac/Rap effects in cytoskeletal rearrangement. Thrombin promotes cytoskeletal changes by both Rho-dependent and -independent (calcium/calmodulin mediated) pathways, resulting in increase in stress fibers and actin-myosin contraction. Rap stimulated by thrombin may serve as a negative feedback to down-regulate Rho and may be required for reigning in thrombin/Rho-induced changes in permeability. Thrombin modulation of endothelial permeability results from the integration of positive and negative signals through Rap and Rho altering junctional and stress fiber components.