Adherens junctions have an important role in the control of vascular permeability. These structures are located at cell-to-cell contacts, mediate cell adhesion and transfer intracellular signals. Adhesion is mediated by cadherins, which interact homophilically in trans and form lateral interactions in cis. VE-cadherin (also known as CDH5 and CD144) is the major component of endothelial adherens junctions and is specific to endothelial cells. Endothelial cells from different types of vessels, such as lymphatic vessels, arteries and veins, show differences in junction composition and organization. Vascular permeability is increased by modifications in the expression and function of adherens junction components. In some cases these defects might be cause of pathology. In this Cell Science at a Glance article, we present the example of the so-called cerebral cavernous malformation (CCM), where adherens junctions are dismantled in the vessels contributing to brain microcirculation. This causes the loss of endothelial cell apical–basal polarity and the formation of cavernomas, which are fragile and hemorrhagic. Other diseases are accompanied by persistent alterations of vascular morphology and permeability, such as seen in tumors. It will be important to achieve a better understanding of the relationship between vascular fragility, malformations and junctional integrity in order to develop more effective therapies.

Endothelial cells are linked one to another by adhesive proteins that are organized in junctional structures. In a way similar to in epithelial cells, the endothelium forms tight junctions (TJs) and adherens junctions (AJs) (Bazzoni and Dejana, 2004; Vestweber et al., 2009; Komarova and Malik, 2010; Niessen et al., 2011). Other adhesive proteins, such as platelet endothelial cell adhesion molecule (PECAM1) and CD146 (also known as MUC18 and MCAM), are concentrated along the intercellular cleft, but in membrane regions outside of TJs or AJs (Bazzoni and Dejana, 2004; Vestweber et al., 2009; Komarova and Malik, 2010).

Cell-to-cell junctions in the endothelium exert the important task of maintaining vascular integrity. Permeability-increasing agents or inflammatory cytokines induce intracellular signals that can cause gap formation at intercellular contacts, to allow cells or solutes to cross the endothelial barrier (Bazzoni and Dejana, 2004; Vestweber et al., 2009; Komarova and Malik, 2010; Nourshargh et al., 2010). In most of the cases, the changes in endothelial permeability are reversible and the gaps close quite rapidly, unless episodes of chronic inflammation occur. Vascular permeability might also increase in more subtle ways. For instance, phosphorylation and partial internalization of junctional adhesive proteins might weaken the junctions and reduce the barrier properties of the endothelium. In these cases, cells remain confluent and most of the junctional architecture is preserved even if the permeability to solutes is significantly increased (Potter et al., 2005; Allingham et al., 2007; Turowski et al., 2008; Kowalczyk and Nanes, 2012; Orsenigo et al., 2012).

Notwithstanding their physiological and pathological relevance, we still know only some of the molecular processes that regulate junction assembly and disassembly. Small GTPases, phosphatases and kinases are implicated, at different levels, in the control of junctional organization and vascular permeability (Noren et al., 2001; Lampugnani et al., 2002; Braga and Yap, 2005; Sakurai et al., 2006; Cain et al., 2010; Stockton et al., 2010; Gloerich and Bos, 2011; Pannekoek et al., 2011). Specific kinases and phosphatases might also associate with junctional proteins and modulate their adhesive properties (Weis et al., 2004; Sui et al., 2005; Grinnell et al., 2010; Broermann et al., 2011; Grinnell et al., 2012; Hatanaka et al., 2012).

Permeability-increasing agents can act through different mechanisms. For instance, inflammatory mediators, including histamine, bradykinin and thrombin, which increase permeability in a fast and reversible way, act through different pathways than cytokines, such as interleukin 1 or tumor necrosis factor, which maintain a high permeability for several days after their induction (Andriopoulou et al., 1999; Noren et al., 2001; Gavard and Gutkind, 2006; Dejana et al., 2008; Gavard, 2009; Harris and Nelson, 2010; Vestweber et al., 2010; Le Guelte et al., 2011; Zhu et al., 2012). Notably, different types of vessels, such as veins, arteries or lymphatics, also present major differences in permeability control (Baluk et al., 2007; Dejana et al., 2009b; McDonald et al., 2011; Orsenigo et al., 2012; Yao et al., 2012).

This Cell Science at a Glance article aims to highlight the specific functional features of junctions in cultured endothelial cells. The focus is mostly on AJs, because we still only have a small amount of information about cell-specific characteristics of TJs in endothelial cells. Examples of the pathological consequences of modifications in AJ structure and function are also discussed.

As shown in the accompanying poster, at TJs, the tetraspannin transmembrane proteins, the claudins, promote tight adhesion between cells. Other proteins at TJs include members of the junctional adhesion molecule (JAM) family, occludin, endothelial-cell-selective adhesion molecule (ESAM) and nectins. At AJs, adhesion is mediated by cadherins, which interact homophilically in trans and form lateral interactions in cis (for reviews, see Bazzoni and Dejana, 2004; Vestweber et al., 2009; Komarova and Malik, 2010; Niessen et al., 2011; Rikitake et al., 2012). With the exception of lymphatic vessels (see below), cadherins create zipper-like structures that maintain stable adhesion between cells (Shapiro et al., 1995).

Although endothelial junctions share several morphological and molecular similarities with junctions of other cell types, they also have important specific features. For instance, the major cadherin that is present at endothelial AJs is vascular endothelial (VE)-cadherin (also known as CDH5 and CD144), which is strictly endothelial specific (Bazzoni and Dejana, 2004). Similarly, claudin 5 is only present at endothelial TJs (Nitta et al., 2003). Plakoglobin in epithelial cells is mostly located at desmosomes, but in endothelial cells, which are devoid of desmosomes, it links VE-cadherin and acts in a way that is similar to β-catenin by promoting the anchorage to actin microfilaments (Bazzoni and Dejana, 2004; Vestweber et al., 2009; Komarova and Malik, 2010). Endothelial cells from different types of vessels can also show differences in junction composition and organization (Orsenigo et al., 2012; Kluger et al., 2013).

The association of AJs to actin is necessary for junction assembly and maintenance. However, the molecular mechanism through which AJs or TJs are anchored to actin microfilaments remains only partially defined. The association of β-catenin to the cytoplasmic tail of cadherins is required for the indirect link between the AJ and actin. Several actin-binding proteins that are located at AJs have been identified and include α-catenin, vinculin, eplin and α-actinin, among others. However, how they reciprocally interact and how they contribute to actin dynamics and anchorage to junctions remains to be fully elucidated (for further details, see Nieset et al., 1997; Weiss et al., 1998; Abe and Takeichi, 2008; Hartsock and Nelson, 2008; Huveneers et al., 2012).

Endothelial cells are strategically located to separate blood from the different tissue compartments. They do this by continuously adapting to the needs of the underlying tissues and by modulating the passage of cells and solutes accordingly.

Stimuli, such as high concentrations of histamine or thrombin, might increase endothelial permeability through an effect on cell contractility that is mediated by phosphorylation of the myosin light chain (Bazzoni and Dejana, 2004; Stockton et al., 2004; Vestweber et al., 2009; Nourshargh et al., 2010). Depending on the strength of cell-to-cell junctions, the retraction of actomyosin can open intercellular gaps, which results in a marked increase in permeability. AJs are also destabilized by the internalization of VE-cadherin. Permeability-increasing agents or inflammatory stimuli induce VE-cadherin phosphorylation at specific tyrosine residues or at Ser665 (Potter et al., 2005; Gavard and Gutkind, 2006; Allingham et al., 2007; Turowski et al., 2008; Kowalczyk and Nanes, 2012; Orsenigo et al., 2012), which promotes the internalization of VE-cadherin through clathrin-coated vesicles.

Other agents such as angiopoietin-1 or fibroblast growth factor (FGF) have been reported to inhibit VE-cadherin internalization and help to maintain vascular integrity (Gavard et al., 2008; Hatanaka et al., 2012). Inhibitors of the non-receptor tyrosine kinase Src reduce VE-cadherin phosphorylation and therefore block an increase in permeability. As discussed below, and shown in the poster, Src induces a strong tyrosine phosphorylation of VE-cadherin (Weis et al., 2004) and activates the internalization machinery (Gavard et al., 2008). Internalization is believed to reduce the amount of VE-cadherin at junctions and thus the endothelial barrier function. The binding of p120-catenin (also known as δ1 catenin) to VE-cadherin maintains VE-cadherin localization at the membrane. This probably occurs through the masking of an endocytic signal sequence thereby preventing VE-cadherin internalization and degradation, and stabilizing the junction (Chiasson et al., 2009; Alcaide et al., 2012; Nanes et al., 2012; Saito et al., 2012).

As shown in the accompanying poster, cadherins can also be ubiquitylated (Fujita et al., 2002; Orsenigo et al., 2012), and this modification might direct their trafficking into different intracellular compartments and, eventually, promote their degradation in proteasomes.

An important question is how endothelial cell junctions are organized in vivo in the different regions of the vascular tree. In large arteries and veins, VE-cadherin and the other members of AJs and TJs are distributed at intercellular contacts in a way that is comparable to that observed in cultured endothelial cells (Orsenigo et al., 2012). By contrast, peripheral lymphatic vessels show striking differences in their junction organization. These vessels drain immune cells and fluids from the surrounding tissues and require a dynamic opening and closure of their endothelial junctions. Although it was previously thought that lymphatic vessels are devoid of adhesive proteins at their junctions, more recent evidence shows that they possess highly specialized junctions that are formed by the same molecular components as those in the blood vessel endothelium but with a strikingly different distribution (Baluk et al., 2007; Dejana et al., 2009b; McDonald et al., 2011; Orsenigo et al., 2012; Yao et al., 2012). TJ- and AJ-adhesive proteins, instead of being organized in zipper-like junctions, are clustered in specific regions (‘button-like junctions’; see poster) that are interspersed with membrane flaps that resemble valve-like structures. Because adhesive proteins are concentrated at the ‘buttons’, the flaps are free to open, resulting in cells and fluids entering the vascular lumen. The flaps, however, also restrain the exit of fluids, thus optimizing the lymph drainage. The presence of adhesive proteins at these buttons is crucial to maintain the overall junctional architecture.

Another important difference among the different types of vessels is the extent of VE-cadherin phosphorylation in vivo. In vitro, in starving and in resting endothelial cells, VE-cadherin phosphorylation is very low but is increased by permeability-increasing agents. In contrast, in vivo, VE-cadherin is constitutively phosphorylated in capillaries and veins, but not in arteries, as shown on the poster (Orsenigo et al., 2012). VE-cadherin phosphorylation is modulated by the hemodynamic conditions and, in particular, the shear stress to which endothelial cells are exposed (Tzima et al., 2005; Conway and Schwartz, 2012; Orsenigo et al., 2012). Shear stress can activate Src, which has a crucial role in inducing and maintaining VE-cadherin phosphorylation in vivo. Phosphorylation of VE-cadherin might act by promoting a rapid and reversible internalization and recycling of the protein when cells are exposed to inflammatory stimuli or permeability-increasing agents (Orsenigo et al., 2012).

Vessels can also acquire specific permeability properties as a consequence of their interactions with surrounding tissues. A typical example is the microvasculature of the brain (Liebner et al., 2011; Paolinelli et al., 2011). These vessels maintain a tight control of permeability to prevent the direct contact of nervous cells with noxious blood components. These endothelial cells, therefore, have complex cell-to-cell junctions that are formed by a particularly well-developed network of TJs and AJs that serve to limit paracellular permeability. On one hand, the passage of nutrients is mediated by a sophisticated system of transporters, which provide glucose and amino acids to the underlying nervous cells. On the other hand, brain endothelial cells also possess a set of negative transporters that exclude toxic agents from their cytoplasm. The high degree of specialization of brain endothelium is maintained by the contact with astrocytes end-feet and pericytes, and together these cells form the so-called neurovascular unit. Conditions that disrupt this structure affect the permeability properties of endothelial cells and induce vascular leakage (Armulik et al., 2010; Liebner et al., 2011; Paolinelli et al., 2011).

It is conceivable that when junctions are dismantled vascular integrity is affected, causing edema and bleeding. Apart from inflammatory agents, junctions can be altered by defects in the expression or function of their molecular components. A typical example is the hereditary and sporadic disease called cerebral cavernous malformation (CCM). CCMs are slow-flow vascular malformations with multiple lumens that are embedded in a thick collagen matrix. CCM occurs as a result of a loss-of-function mutation in any one of three genes encoding the CCM proteins, CCM1 (also known as Krev interaction trapped protein 1, KRIT1), CCM2 (also known as malcavernin, MGC4607) or CCM3 (also known as programmed cell death protein 10, PDCD10) (Labauge et al., 2007; Dejana et al., 2009a; Kleaveland et al., 2009; Whitehead et al., 2009; Boulday et al., 2011; McDonald et al., 2012). Co-immunoprecipitation experiments show that the three CCM proteins form a tripartite complex in the cytoplasm (Zawistowski et al., 2005), which might explain why the loss of any of them leads to the inactivation of the complex and causes vascular malformations that are similar in morphology. CCM proteins are ubiquitously expressed, but only the endothelial-cell-specific deletions of CCMs lead to the disease in experimental animals, suggesting that these malformations are caused by their dysfunction specifically in endothelial cells. Inactivation of these proteins in other cell types does not cause cavernomas (Boulday et al., 2009).

Importantly, the CCM complex might associate (through CCM1) with β-catenin and the actin-binding protein afadin (also known as AF6), and colocalizes with VE-cadherin at endothelial AJs (Glading et al., 2007; Glading and Ginsberg, 2010). CCM1 is an effector of the small GTPase Rap1, which is known to stabilize junctions; activated Rap1 promotes localization of CCM1 to junctions and this process is required for junction stability (Glading et al., 2007). Furthermore, CCM2 is involved in the Rho GTPase pathway, which is also known to regulate junction integrity (Whitehead et al., 2009; McDonald et al., 2012; Richardson et al., 2013). Therefore, the CCM complex might have an important role in maintaining the correct architecture of endothelial junctions. Indeed, ablation of any CCM protein strongly affects AJs, AJ permeability and, most importantly, vascular fragility is markedly increased, resulting in lesions that frequently bleed and cause headache, seizures and eventually hemorrhagic stroke in the affected patients (Riant et al., 2010; Boulday et al., 2011). It has also been shown that upon loss of one CCM complex component, VE-cadherin and other AJ factors do not correctly localize to the basolateral side of the endothelial membrane but, instead, are diffusely localized on the cell membrane (Lampugnani et al., 2010). Under resting conditions, VE-cadherin interacts and colocalizes with members of the Par polarity complex (consisting of PAR3, PAR6 and protein kinase Cζ, PKCζ) (Iden et al., 2006; Lampugnani et al., 2010) and is required for the activation of PKCζ. Dismantling AJs by inactivation of CCM1 leads to the abrogation of endothelial polarity, which might explain why CCM-mediated lesions are abnormally enlarged and present multiple lumens. When CCM expression is reduced or abrogated, podocalixin, a marker of the apical membrane domain of the endothelium, and collagen IV, which marks the basal side of the membrane, are delocalized, not only in cell culture, but in the vascular malformations of patients and animal models (Lampugnani et al., 2010). The loss of endothelial polarity is probably due to altered localization of the Par polarity complex due to dismantling of the junction (Lampugnani et al., 2010) (see poster).

CCM is one of the first conditions described that shows that altered junction composition or organization can affect vascular morphogenesis and be the cause of severe pathologies. Other diseases might be accompanied by persistent alterations of vascular morphology and their permeability, such as seen in tumors. Cancer cells produce high amounts of growth factors and, in particular, vascular endothelial growth factor (VEGF), which strongly increases vascular permeability (Potente et al., 2011). This has important consequences for the capacity of tumor cells to enter the circulation and metastasize. The permeable and fragile tumor vessels also cause hemorrhages and edema, which creates compression and results in areas of poor perfusion leading to tissue necrosis. This is important, as in these regions, chemotherapeutics cannot easily reach the surviving tumor cells (Potente et al., 2011). Normalizing the tumor vasculature through different approaches, including reshaping of junctions, is therefore an attractive anticancer strategy, at least during specific steps of tumor progression.

During the past few years, our knowledge of the molecular organization of endothelial junctions has been increased substantially. Several new junctional components have been identified, although their precise functions and reciprocal interactions remain to be understood in detail. However, a lot of work is needed before we understand how the defects in junction structure and function act as the underlying cause of pathology. In vitro studies are crucial to understand the basic cell biology of endothelial cell junction formation, but clinical studies are also needed to identify the genetic basis of vascular malformations and to understand how the defects in endothelial integrity develop in human patients. It will be important to integrate these different approaches to achieve a better understanding of the etiology of vascular malformation and of junctional integrity disorders in order to develop more effective therapies.

Funding

The work of our laboratory is supported by grants from the Fondation Leducq Transatlantic Network of Excellence; Associazione Italiana per la Ricerca sul Cancro (AIRC); the ‘Special Program Molecular Clinical Oncology 5×1000’ to AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM); the European Union [EUSTROKE-contract-202213, OPTISTEM-contract-223098, ANGIOSCAFF-NMP3-LA-2008-214402; networks ENDOSTEM-HEALTH-2009-241440, JUSTBRAIN-HEALTH-2009-241861, ITN Vessels]; the European Research Council; and the CARIPLO Foundation.

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