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This study utilized complementary approaches including siRNA knockdown, culturing in Ca<jats:sup>2+<\/jats:sup>\u2010free medium, and VE\u2010cadherin blocking antibody to alter VE\u2010cadherin extracellular interactions to investigate the role of VE\u2010cadherin outside\u2010in signaling in modulation of Rac activation and EC barrier regulation by prostacyclin analog iloprost. Spatial analysis of Rac activation in pulmonary EC by FRET revealed additional spike in iloprost\u2010induced Rac activity at the sites of newly formed cell\u2013cell junctions. In contrast, disruption of VE\u2010cadherin extracellular trans\u2010interactions suppressed iloprost\u2010activated Rac signaling and attenuated EC barrier enhancement and cytoskeletal remodeling. These inhibitory effects were associated with decreased membrane accumulation and activation of Rac\u2010specific guanine nucleotide exchange factors (GEFs) Tiam1 and Vav2. Conversely, plating of pulmonary EC on surfaces coated with extracellular VE\u2010cadherin domain further promoted iloprost\u2010induced Rac signaling. In the model of thrombin\u2010induced EC barrier recovery, blocking of VE\u2010cadherin trans\u2010interactions attenuated activation of Rac pathway during recovery phase and delayed suppression of Rho signaling and restoration of EC barrier properties. These results suggest that VE\u2010cadherin outside\u2010in signaling controls locally Rac activity stimulated by barrier protective agonists. This control is essential for maximal EC barrier enhancement and accelerated barrier recovery. J. Cell. 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