Regulation of cell-cell contacts is essential for integrity of the vascular endothelium. Here, a critical role of the F-actin binding protein drebrin in maintaining endothelial integrity is revealed under conditions mimicking vascular flow. Drebrin knockdown leads to weakening of cell-cell contacts, characterized by loss of nectin from adherens junctions and its subsequent lysosomal degradation. Immunoprecipitation, FRAP and mitochondrial retargeting experiments show that nectin stabilization occurs through a chain of interactions: drebrin binding to F-actin, interaction of drebrin and afadin through their polyproline and PR1-2 regions, and recruitment of nectin through afadin's PDZ region. Key elements are drebrin's modules that confer binding to afadin and F-actin. Evidence is provided by constructs containing afadin's PDZ region coupled to drebrin's F-actin binding region or to lifeact, which restore junctional nectin under knockdown of drebrin or of both drebrin and afadin. Drebrin, containing binding sites for both afadin and F-actin, is thus uniquely equipped to stabilize nectin at endothelial junctions and to preserve endothelial integrity under vascular flow.