Plakoglobin transmits tension across VE-cadherin for vascular leak formation and leukocyte diapedesis.

VE-cadherin controls endothelial junction integrity, and thereby inflammation-induced vascular permeability and leukocyte extravasation. The adhesive function of VE-cadherin is influenced by its binding to β-catenin, which is linked by α-catenin to actin. Plakoglobin can replace β-catenin in such complexes, and both types of complexes co-exist in endothelial cells. Here, we have investigated whether β-catenin and plakoglobin differ in their relevance for controlling endothelial junctions. Based on gene silencing in vitro and conditional endothelium-specific gene inactivation in mice in vivo, we found that both leukocyte diapedesis through endothelium and induction of vascular permeability by inflammatory mediators depend on plakoglobin, but not β-catenin. Mechanistically, we demonstrated that plakoglobin is crucial for the generation of tension across VE-cadherin by transmigrating leukocytes and by inflammatory mediators, whereas β-catenin was dispensable in this context. Transgenic mice expressing a VE-cadherin tension sensor revealed that plakoglobin is essential in vivo for histamine-induced tension across VE-cadherin. Thus, plakoglobin, but not β-catenin, is needed for leukocyte diapedesis, the induction of vascular permeability, and the stimulation of mechanical tension across VE-cadherin.