Endothelial cell–cell junctions: happy together

Endothelial cells function as gatekeepers that control the infiltration of leukocytes and plasma proteins into the walls of blood vessels. This control is achieved, to a large extent, through the coordinated opening and closure of cell–cell junctions.Junctions are not only sites of cell–cell attachment but can also function as signalling structures that communicate cell position, limit growth and apoptosis, and regulate vascular homeostasis.Junctional complexes trigger intracellular signals directly, by engaging signalling proteins or growth-factor receptors, or indirectly, by tethering and retaining transcription factors at the cell membrane, thereby limiting their nuclear translocation.Endothelial cells express both adherens and tight junctions, which are formed by different components. In both types of junction, cell–cell adhesion is due to transmembrane adhesive proteins that promote homophilic interactions and form a pericellular zipper-like structure along the cell border.At adherens junctions, endothelial cell adhesion is mediated by vascular endothelial cadherin (VE-cadherin), which is linked to intracellular proteins such as β-catenin, plakoglobin and p120. At tight junctions, adhesion is due to members of the claudin family, which are associated with different intracellular proteins such as zona occludens-1 (ZO1).Other adhesive proteins present at tight junctions are occludin and the members of the junctional adhesion molecule (JAM) family.The organization of adherens and tight junctions requires the nectin–afadin complex. Platelet endothelial cell adhesion molecule (PECAM) is an endothelial junctional component that is located outside adherens and tight junctions.Junctions are required to maintain the integrity of the vessel wall. Modification of the molecular organization and intracellular signalling of junctional proteins might have complex effects on vascular homeostasis.Junctional proteins have an important role in angiogenesis, by modulating cell growth, apoptosis and tubulogenesis. Inactivation of the genes that encode some junctional components prevents normal vascular development in the embryo.Leukocyte infiltration into inflamed regions most frequently occurs through endothelial junctions. The molecular basis of this phenomenon is still largely unknown but it is likely that, on adhesion to inflamed endothelium, leukocytes transfer signals that direct junction rearrangement and promote leukocyte diapedesis.