Stabilizing the VE-cadherin-catenin complex blocks leukocyte extravasation and vascular permeability

• Published in: The EMBO journal 2011-10, Vol.30 (20), p.4157-4170
• Main Authors: Schulte, Dörte, Küppers, Verena, Dartsch, Nina, Broermann, Andre, Li, Hang, Zarbock, Alexander, Kamenyeva, Olena, Kiefer, Friedemann, Khandoga, Alexander, Massberg, Steffen, Vestweber, Dietmar
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - metabolism; alpha Catenin - genetics; alpha Catenin - metabolism; Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Cadherins - genetics; Cadherins - metabolism; Capillary Permeability; Cells; Cells, Cultured; diapedesis; EMBO05; EMBO19; endothelial junctions; Endothelium, Vascular - metabolism; Female; Gene Knock-In Techniques; Histamine; Inflammation - genetics; Inflammation - metabolism; Intercellular Junctions - metabolism; leukocyte trafficking; Leukocytes; Leukocytes - metabolism; Leukocytes - physiology; Lung - metabolism; Lymph nodes; Lymph Nodes - metabolism; Lymphocytes; Male; Mice; Muscle, Skeletal - metabolism; Rodents; Skin - metabolism; Transendothelial and Transepithelial Migration; Vascular endothelial growth factor; VE-cadherin
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2011.304

To determine whether leukocytes need to open endothelial cell contacts during extravasation, we decided to generate mice with strongly stabilized endothelial junctions. To this end, we replaced VE‐cadherin genetically by a VE‐cadherin–α‐catenin fusion construct. Such mice were completely resistant to the induction of vascular leaks by VEGF or histamine. Neutrophil or lymphocyte recruitment into inflamed cremaster, lung and skin were strongly inhibited in these mice, documenting the importance of the junctional route in vivo . Surprisingly, lymphocyte homing into lymph nodes was not inhibited. VE‐cadherin–α‐catenin associated more intensely with the actin cytoskeleton as demonstrated by its membrane mobility and detergent extractability. Our results establish the junctional route as the main pathway for extravasating leukocytes in several, although not in all tissues. Furthermore, in these tissues, plasticity of the VE‐cadherin–catenin complex is central for the leukocyte diapedesis mechanism. Leukocyte exit from the bloodstream involves crossing the endothelial barrier. Both trans‐ and paracellular routes have been proposed for transmigration. Preventing opening of intercellular junctions blocks extravasation ‐ providing strong evidence for the importance of the paracellular route.