Endothelial barrier maintenance is important for the normal function of tissues, and transient disruptions of endothelial adherens junctions (AJs) and associated changes in the cytoskeleton can contribute to the pathogenesis of diseases, such as inflammation, edema, stroke and cancer. Vascular endothelial growth factor (VEGF) is one of the key factors that regulate the permeability of endothelial AJs by promoting the phosphorylation of VE-cadherin (also known as CDH5) by Src kinases, which results in junction opening. Nitric oxide (NO) that is produced by endothelial NO synthase (eNOS) has been shown to have an effect on VEGF and on endothelial permeability, but the underlying molecular mechanisms are not clear. On page 5541, William Sessa and colleagues show that loss of NO through silencing of eNOS in human endothelial cells, surprisingly, stabilises cortical actin structures. This is achieved through increased interaction of VE-cadherin with TIAM1, a guanine nucleotide exchange factor for Rac, at the cell junctions. As the authors show here, this leads to an increase in Rac activity, which in turn promotes the assembly of cortical actin at junctions. Taken together, the data presented in this work suggest that eNOS-derived NO is a key factor in regulating reversible changes in endothelial cell permeability by fine-tuning the level of small GTPases that control VE-cadherin-mediated changes in the junctional cytoskeleton.