Perspectives Series: Cell Adhesion in Vascular Biology Endothelial Adherens Junctions: Implications in the Control of Vascular Permeability and Angiogenesis

Introduction The endothelium is a continuous monolayer formed by cells linked to each other by different types of adhesive structures. These are involved in the control of vascular permeability to plasma proteins and circulating cells, and contribute to the establishment of cell polarity by limiting the diffusion of lipid and transmembrane proteins in the outer leaflet of the plasma membrane bilayer (1). A major ubiquitous type of endothelial cell–cell junctions are adherens junctions. The general organization of adherens junctions presents many structural and functional similarities in different cell types but its molecular components and biological meaning may vary in the different tissues. In recent years excellent reviews (3–9) have extensively considered the molecular organization and signaling properties of adherens junctions. The present review is devoted to the special properties of these structures in the endothelium and offers some insights on their role in the control of endothelial cell permeability and vascular morphogenesis. Adherens junctions are formed by transmembrane adhesive proteins, belonging to the cadherin family, that are organized in clusters at cell–cell contacts and connect through their cytoplasmic domain with a complex network of cytoskeletal proteins (3–9). Cadherins are single chain transmembrane polypeptides that promote, at least in the majority of cases, homophilic type of binding. The extracellular domain of cadherins usually consists of five homologous repeats of 110 residues which contain putative Ca 2 1 binding sequences. The cadherin short cytoplasmic region interacts with three related proteins which belong to the “armadillo” family ( b -catenin, plakoglobin, and p120). b -catenin and plakoglobin bind a -catenin, which is homologous to vinculin and mediates the linkage of the cadherin–catenin complex to the actin cytoskeleton (Fig. 1). This complex organization of cadherin-catenins and the cytoskeleton is necessary not only to strengthen cell–cell adhesion but also to transfer signals between neighboring cells (3–9). Adherens junctions can do so in different ways. First, they can act by localizing signaling molecules and thereby facilitating their reciprocal interaction through an increased proximity effect. Kinases (such as src, lyn, and yes), tyrosine phosphatases, components of the Ras signaling pathways, and small GTP binding proteins concentrate at cell–cell contacts in correspondence of adherens junctions (3–9). Second, adherens junctions may play a more direct role in signaling by controlling the cytoplasmic levels of catenins. There is evidence that b -catenin and plakoglobin can act as signaling molecules when released into the cytosol from adherens junctions. As other members of the “armadillo” family, both proteins can translocate to the nucleus, bind transcription factor(s) and control gene expression (10, 11). In addition, cytosolic b -catenin and plakoglobin can associate with “adenomatous polyposis coli” (APC) 1 an oncogene which inhibits cell cycle progression (6–9) (Fig. 1). Finally, adherens junctions, by attaching cells to one another, allow justacrine signaling through the local release and binding of growth factors and cytokines.