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• W2010045296 abstract "Human pathologies such as vascular malformations, hemorrhagic stroke, and edema have been associated with defects in the organization of endothelial cell junctions. Understanding the molecular basis of these diseases requires different integrated approaches which include basic cell biology, clinical studies, and studies in animal models such as mice and zebrafish. In this review we discuss recent findings derived from these approaches and their possible integration in a common picture. Human pathologies such as vascular malformations, hemorrhagic stroke, and edema have been associated with defects in the organization of endothelial cell junctions. Understanding the molecular basis of these diseases requires different integrated approaches which include basic cell biology, clinical studies, and studies in animal models such as mice and zebrafish. In this review we discuss recent findings derived from these approaches and their possible integration in a common picture. A variety of human vascular pathologies are due to or exacerbated by altered control of endothelial permeability. Defects in endothelial permeability can lead to edema and increase in interstitial pressure, which in turn induces compression and altered tissue perfusion. A typical example is ischemic stroke, where edema around the ischemic area extends brain damage. Inflammation is also associated with increases in vascular permeability, which favors leukocyte diapedesis through the vessel wall but may create pain and swelling. Edema is usually a reversible condition and the control of vascular permeability may be restored once the triggering cause is removed. However, there are extreme conditions where the integrity of the endothelial monolayer is severely affected, cell-to-cell junctions are disrupted, and endothelial cells detach from the vessel wall, creating areas of vascular damage and possibly microthrombi. Altered permeability may also be accompanied by vascular fragility with the frank rupture of the vessels and formation of hemorrhages. This is a frequent condition in tumors where the newly forming vasculature is usually permeable and fragile (Carmeliet and Jain, 2000Carmeliet P. Jain R.K. Angiogenesis in cancer and other diseases.Nature. 2000; 407: 249-257Crossref PubMed Scopus (7006) Google Scholar). In other more rare cases though, increased vascular fragility may be due to congenital alterations in vascular development (Brouillard and Vikkula, 2003Brouillard P. Vikkula M. Vascular malformations: localized defects in vascular morphogenesis.Clin. Genet. 2003; 63: 340-351Crossref PubMed Scopus (75) Google Scholar, Brouillard and Vikkula, 2007Brouillard P. Vikkula M. Genetic causes of vascular malformations.Hum. Mol. Genet. 2007; 16: R140-R149Crossref PubMed Scopus (169) Google Scholar). Molecular cloning of the defective genes from human disorders and gene inactivation approaches in model organisms such as mouse and fish have resulted in the identification of many genes involved in vascular remodeling and maintenance of vascular integrity. Deletion or reduced expression of these genes may result in early lethality due to diffuse hemorrhages in the embryo. However, in other cases the vascular defect may remain silent during development but manifest in the adult when the vessels are exposed to a triggering condition. Defects in vascular permeability can have a number of different causes. Vascular permeability is mediated by at least two broad mechanisms, called the paracellular and transcellular pathways. The first is controlled by the dynamic opening and closing of endothelial junctions (Dejana et al., 2008Dejana E. Orsenigo F. Lampugnani M.G. The role of adherens junctions and VE-cadherin in the control of vascular permeability.J. Cell Sci. 2008; 121: 2115-2122Crossref PubMed Scopus (651) Google Scholar), while the second includes vesicular transport systems, fenestrae, and biochemical transporters (Dvorak et al., 1996Dvorak A.M. Kohn S. Morgan E.S. Fox P. Nagy J.A. Dvorak H.F. The vesiculo-vacuolar organelle (VVO): a distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation.J. Leukoc. Biol. 1996; 59: 100-115PubMed Google Scholar). Vascular fragility can be due to an altered organization of intercellular junctions and/or defective interaction of endothelial cells with pericytes or matrix proteins. The focus of this review is primarily on the role of intercellular junctions in the control of vascular permeability and integrity. We discuss current knowledge regarding the molecular and functional organization of adherens (AJ) and tight junctions (TJ), and attempt to show the correlations between experimental studies and related human pathologies. The detailed architecture of endothelial cell-cell junctions has been described in detail in several other recent reviews (Bazzoni and Dejana, 2004Bazzoni G. Dejana E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis.Physiol. Rev. 2004; 84: 869-901Crossref PubMed Scopus (859) Google Scholar, Gonzalez-Mariscal et al., 2008Gonzalez-Mariscal L. Tapia R. Chamorro D. Crosstalk of tight junction components with signaling pathways.Biochim. Biophys. Acta. 2008; 1778: 729-756Crossref PubMed Scopus (500) Google Scholar, Wallez and Huber, 2008Wallez Y. Huber P. Endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesis.Biochim. Biophys. Acta. 2008; 1778: 794-809Crossref PubMed Scopus (275) Google Scholar) In Figure 1 we show a simplified version of some of the most important molecules involved in endothelial junction organization (Bazzoni and Dejana, 2004Bazzoni G. Dejana E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis.Physiol. Rev. 2004; 84: 869-901Crossref PubMed Scopus (859) Google Scholar, Vestweber, 2008Vestweber D. VE-cadherin: the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 223-232Crossref PubMed Scopus (464) Google Scholar, Weber et al., 2007Weber C. Fraemohs L. Dejana E. The role of junctional adhesion molecules in vascular inflammation.Nat. Rev. Immunol. 2007; 7: 467-477Crossref PubMed Scopus (368) Google Scholar). Endothelial cells have at least two specialized adhesive junctional regions that are comparable to adherens junctions (AJs) and tight junctions (TJs) found in epithelial cells. In contrast to epithelial cells, however, endothelial cells lack typical desmosomes. Gap junctions are also present in the endothelium and play an important role in different endothelial functions but, as far as we know, are not involved in control of endothelial permeability and, for simplicity, will not be further considered in this review. AJs and TJs have different functions. AJs initiate cell-to-cell contacts and promote their maturation and maintenance. TJs regulate the passage of ions and solutes through the paracellular route (Bazzoni and Dejana, 2004Bazzoni G. Dejana E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis.Physiol. Rev. 2004; 84: 869-901Crossref PubMed Scopus (859) Google Scholar, Gonzalez-Mariscal et al., 2008Gonzalez-Mariscal L. Tapia R. Chamorro D. Crosstalk of tight junction components with signaling pathways.Biochim. Biophys. Acta. 2008; 1778: 729-756Crossref PubMed Scopus (500) Google Scholar). TJs may also act as a membrane “fence” to limit the free movement of lipids and proteins between the apical and the basolateral cell surfaces. Most importantly, both structures can transfer intracellular signals that control many endothelial cell functions. The organization of intercellular junctions through the clustering of adhesion and signaling proteins is therefore an important process through which the cells sense their position, control growth and apoptosis, and form tubular structures (see below) (Matter and Balda, 2003Matter K. Balda M.S. Signalling to and from tight junctions.Nat. Rev. Mol. Cell Biol. 2003; 4: 225-236Crossref PubMed Scopus (677) Google Scholar, Bazzoni and Dejana, 2004Bazzoni G. Dejana E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis.Physiol. Rev. 2004; 84: 869-901Crossref PubMed Scopus (859) Google Scholar, Dejana, 2004Dejana E. Endothelial cell-cell junctions: happy together.Nat. Rev. Mol. Cell Biol. 2004; 5: 261-270Crossref PubMed Scopus (833) Google Scholar, Gonzalez-Mariscal et al., 2008Gonzalez-Mariscal L. Tapia R. Chamorro D. Crosstalk of tight junction components with signaling pathways.Biochim. Biophys. Acta. 2008; 1778: 729-756Crossref PubMed Scopus (500) Google Scholar). Although the molecular components of TJs and AJs are different, they do have common features (Figure 1). In both types of junction, adhesion is mediated by transmembrane proteins that promote homophilic interactions and form a pericellular zipper-like structure along the cell border through their lateral aggregation in trans and cis (for review Bazzoni and Dejana, 2004Bazzoni G. Dejana E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis.Physiol. Rev. 2004; 84: 869-901Crossref PubMed Scopus (859) Google Scholar, Gonzalez-Mariscal et al., 2008Gonzalez-Mariscal L. Tapia R. Chamorro D. Crosstalk of tight junction components with signaling pathways.Biochim. Biophys. Acta. 2008; 1778: 729-756Crossref PubMed Scopus (500) Google Scholar, Wallez and Huber, 2008Wallez Y. Huber P. Endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesis.Biochim. Biophys. Acta. 2008; 1778: 794-809Crossref PubMed Scopus (275) Google Scholar) Endothelial cells express cell-type-specific transmembrane adhesion proteins such as VE-cadherin at AJs and claudin-5 at TJs. The restricted cell specificity of these components indicates that they might be needed for selective cell-cell recognition and/or specific functional properties of endothelial cells. Through their cytoplasmic tails, adhesion proteins of both types of junctions bind to cytoskeletal and signaling proteins that promote anchoring of junctions to actin microfilaments and transfer of intracellular signals to the inside of the cell. Cytoskeletal association is required for stabilization of the junctions, but also for the dynamic regulation of junction opening and closing. The interaction of junctional adhesion proteins with the actin cytoskeleton is also relevant in the maintenance of cell shape and polarity (Hartsock and Nelson, 2008Hartsock A. Nelson W.J. Adherens and tight junctions: structure, function and connections to the actin cytoskeleton.Biochim. Biophys. Acta. 2008; 1778: 660-669Crossref PubMed Scopus (850) Google Scholar). Many reports support the concept that AJs and TJs are interconnected and that AJs influence TJ organization (see below). AJs are formed at early stages of intercellular contacts and are followed by TJ organization. Some TJ components such as ZO-1 are found in AJs at early stages of junction formation and concentrate in TJs only subsequently when junctions are stabilized. Interestingly, however, AJs are required for TJ assembly but are dispensable for TJ maintenance in epithelial cells (Capaldo and Macara, 2007Capaldo C.T. Macara I.G. Depletion of E-cadherin disrupts establishment but not maintenance of cell junctions in Madin-Darby canine kidney epithelial cells.Mol. Biol. Cell. 2007; 18: 189-200Crossref PubMed Scopus (199) Google Scholar). As described in the legend to Figure 1, the core components of TJs that promote cell-to-cell adhesion are members of the claudin family (Van Itallie and Anderson, 2006Van Itallie C.M. Anderson J.M. Claudins and epithelial paracellular transport.Annu. Rev. Physiol. 2006; 68: 403-429Crossref PubMed Scopus (857) Google Scholar, Furuse and Tsukita, 2006Furuse M. Tsukita S. Claudins in occluding junctions of humans and flies.Trends Cell Biol. 2006; 16: 181-188Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar). The claudin family has more than 20 members, only a few of which are expressed by endothelial cells. Claudin-5 is rather ubiquitous along the vascular tree. Other non-cell-specific claudins are also found in endothelial cells and their combination varies to respond to the different needs of the perfused organ. A variety of additional adhesion transmembrane proteins can also be found at TJs (JAMs, ESAM, occludin, etc.) and these contribute to intercellular adhesion in different ways (see below) (Wallez and Huber, 2008Wallez Y. Huber P. Endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesis.Biochim. Biophys. Acta. 2008; 1778: 794-809Crossref PubMed Scopus (275) Google Scholar). Multiple intracellular partners of TJ adhesive proteins have been described. Among the best characterized are the members of the ZO family (ZO1 and 2 in the endothelium), a closely related subgroup of the membrane associated guanylate kinase (MAGUK) family that localize at TJs in most tissues including the endothelium. Other intracellular TJ proteins include signaling and actin-binding proteins. At AJs, adhesion is mediated by members of the cadherin family. VE-cadherin is expressed in essentially all types of vessels. N-cadherin is also present in the endothelium, but is frequently found localizing to non-AJ cellular structures both in vitro and in vivo. VE- and N-cadherins both bind catenins, in particular p120, β-catenin, and plakoglobin. β-catenin also binds α-catenin, which when released from junctions into the cytosol promotes actin bundling. As for TJs, many other actin-binding proteins and several kinases and phosphatases are also found at AJs (Wallez and Huber, 2008Wallez Y. Huber P. Endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesis.Biochim. Biophys. Acta. 2008; 1778: 794-809Crossref PubMed Scopus (275) Google Scholar, Bazzoni and Dejana, 2004Bazzoni G. Dejana E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis.Physiol. Rev. 2004; 84: 869-901Crossref PubMed Scopus (859) Google Scholar, Vestweber, 2008Vestweber D. VE-cadherin: the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 223-232Crossref PubMed Scopus (464) Google Scholar). The organization of TJs and AJs varies along the vascular tree depending on the functional needs of the vessels. For instance, TJs are particularly abundant and complex in the brain microcirculation where there is a need to strictly control permeability, whereas the junctions are relatively poorly organized in postcapillary venules where exchange between blood and tissues is quite dynamic (Engelhardt, 2003Engelhardt B. Development of the blood-brain barrier.Cell Tissue Res. 2003; 314: 119-129Crossref PubMed Scopus (253) Google Scholar, Dejana, 2004Dejana E. Endothelial cell-cell junctions: happy together.Nat. Rev. Mol. Cell Biol. 2004; 5: 261-270Crossref PubMed Scopus (833) Google Scholar). An example of highly specialized junctions is found in peripheral lymphatic vessels, where intercellular junctions between lymphatic endothelial cells control entry of fluid and cells that drain from surrounding tissues. These lymphatic capillaries possess highly specialized junctions that, although formed by the same molecular components as blood vessels, have a strikingly different morphology. Endothelial borders have discontinuous button-like junctions with intermingled flaps resembling valve-like structures (Baluk et al., 2007Baluk P. Fuxe J. Hashizume H. Romano T. Lashnits E. Butz S. Vestweber D. Corada M. Molendini C. Dejana E. et al.Functionally specialized junctions between endothelial cells of lymphatic vessels.J. Exp. Med. 2007; 204: 2349-2362Crossref PubMed Scopus (589) Google Scholar). At the molecular level, AJ and TJ proteins are concentrated at the buttons, leaving the flaps free to open without disrupting the overall junctional organization. The larger, more proximal collecting lymphatic vessels have continuous zipper-like junctions resembling those in the endothelium of blood vessels. An important emerging concept is that intercellular junctions are dynamic structures undergoing continuous remodeling not only during morphogenesis in the embryo or upon exposure of cells to agents that increase permeability, but also in confluent and resting cells. Continuous recycling of adhesive proteins and signaling partners may occur at AJs and also at TJs. Cadherins, and in particular VE-cadherin, show a flow-like movement in a basal to apical direction which is accompanied by actin reorganization (Kametani and Takeichi, 2007Kametani Y. Takeichi M. Basal-to-apical cadherin flow at cell junctions.Nat. Cell Biol. 2007; 9: 92-98Crossref PubMed Scopus (165) Google Scholar). Furthermore, recent data have shown that in Drosophila E-cadherin forms stable adhesion foci that undergo continuous, actin-controlled, mobility along intercellular contacts (Cavey et al., 2008Cavey M. Rauzi M. Lenne P.F. Lecuit T. A two-tiered mechanism for stabilization and immobilization of E-cadherin.Nature. 2008; 453: 751-756Crossref PubMed Scopus (295) Google Scholar). All of this suggests that even apparently stable AJs are dynamic structures able to continuously adapt to tissue requirements. The endothelium is continuously exposed to hemodynamic stimuli such as shear stress or the rhythmic changes in pressure due to heart beating, as well as vessel contraction and dilation. Junctions and the cell cytoskeleton need to continuously reshape to allow the endothelial monolayer to adapt to the dynamic conditions to which it is exposed. Junctional proteins such as VE-cadherin may also serve as flow sensors and transfer intracellular stimuli which help the cell to react to changes in flow conditions (Tzima et al., 2005Tzima E. Irani-Tehrani M. Kiosses W.B. Dejana E. Schultz D.A. Engelhardt B. Cao G. DeLisser H. Schwartz M.A. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress.Nature. 2005; 437: 426-431Crossref PubMed Scopus (1138) Google Scholar). As discussed above, the role of junctions in endothelial and epithelial cell permeability is now well established, and these are clearly highly dynamic structures regulated in response to environmental conditions. A number of recent studies have focused on the importance of claudins in TJ formation and maintenance (Furuse and Tsukita, 2006Furuse M. Tsukita S. Claudins in occluding junctions of humans and flies.Trends Cell Biol. 2006; 16: 181-188Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar, Van Itallie and Anderson, 2006Van Itallie C.M. Anderson J.M. Claudins and epithelial paracellular transport.Annu. Rev. Physiol. 2006; 68: 403-429Crossref PubMed Scopus (857) Google Scholar). Although inactivation of claudin-5 gene in mice did not morphologically alter the vascular network or the ultrastructural appearance of TJs, claudin-5-deficient pups died within 10 hr of birth due to a size-selective loosening of the blood-brain barrier against molecules less than 800 Da. Other claudins may form the TJ strands in claudin-5 mutants and maintain the barrier against larger molecules (Furuse and Tsukita, 2006Furuse M. Tsukita S. Claudins in occluding junctions of humans and flies.Trends Cell Biol. 2006; 16: 181-188Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar). Claudin-3 is likely responsible for the complex organization of TJ in brain vessels. Claudin-3 and -5 therefore appear to act in concert to form the tightly organized strand network at TJs of the brain microcirculation. Gene inactivation of claudin-1, which is also expressed in endothelial cells, did not result in a vascular phenotype during embryonic development, suggesting that it plays a lesser role in TJ in endothelium compared to claudin-5 and -3 (Gonzalez-Mariscal et al., 2008Gonzalez-Mariscal L. Tapia R. Chamorro D. Crosstalk of tight junction components with signaling pathways.Biochim. Biophys. Acta. 2008; 1778: 729-756Crossref PubMed Scopus (500) Google Scholar). Occludin is another transmembrane protein structurally similar to claudins, although not strongly homologous at the sequence level, which becomes incorporated into claudin-based junctional strands. Occludin is present in endothelial cells and in particular in the brain (Hirase et al., 1997Hirase T. Staddon J.M. Saitou M. Ando-Akatsuka Y. Itoh M. Furuse M. Fujimoto K. Tsukita S. Rubin L.L. Occludin as a possible determinant of tight junction permeability in endothelial cells.J. Cell Sci. 1997; 110: 1603-1613Crossref PubMed Google Scholar). However, no effects on vascular morphology or blood-brain barrier permeability have been reported in mice lacking occludin. Junction adhesion molecule-A (JAM-A) and its related family members JAM-B, JAM-C, endothelial cell-selective adhesion molecule (ESAM), and cocksackie- and adeno-virus receptor (CAR) are transmembrane glycoproteins that associate with TJ strands but are not part of the strands per se (Weber et al., 2007Weber C. Fraemohs L. Dejana E. The role of junctional adhesion molecules in vascular inflammation.Nat. Rev. Immunol. 2007; 7: 467-477Crossref PubMed Scopus (368) Google Scholar). All JAM family members and ESAM are expressed in endothelial cells, but inactivation of their respective genes in mice does not cause any defect in the development of the vascular system in the embryo (Weber et al., 2007Weber C. Fraemohs L. Dejana E. The role of junctional adhesion molecules in vascular inflammation.Nat. Rev. Immunol. 2007; 7: 467-477Crossref PubMed Scopus (368) Google Scholar, Wegmann et al., 2006Wegmann F. Petri B. Khandoga A.G. Moser C. Khandoga A. Volkery S. Li H. Nasdala I. Brandau O. Fassler R. et al.ESAM supports neutrophil extravasation, activation of Rho, and VEGF-induced vascular permeability.J. Exp. Med. 2006; 203: 1671-1677Crossref PubMed Scopus (176) Google Scholar). In adult mice, all these molecules play an important role in modulating leukocyte diapedesis through endothelial cells. Unlike other junctional proteins, JAM-C increases endothelial permeability when expressed at the endothelial cell surface, suggesting it may play a role in promoting and/or organizing junction formation (Orlova et al., 2006Orlova V.V. Economopoulou M. Lupu F. Santoso S. Chavakis T. Junctional adhesion molecule-C regulates vascular endothelial permeability by modulating VE-cadherin-mediated cell-cell contacts.J. Exp. Med. 2006; 203: 2703-2714Crossref PubMed Scopus (133) Google Scholar). This activity is mediated by changes in actin organization and VE-cadherin activity. Several kinases and phosphatases have been shown to modulate TJ protein phosphorylation and endothelial permeability in vitro and in some conditions also in vivo. AJs, and the AJ component VE-cadherin in particular, play an important role in the control of vascular permeability and integrity. In vivo data using blocking antibodies to VE-cadherin show profound alterations of lung and heart vascular permeability accompanied by endothelial cell retraction and partial detachment with exposure of the subendothelial matrix (for review see Dejana et al., 2008Dejana E. Orsenigo F. Lampugnani M.G. The role of adherens junctions and VE-cadherin in the control of vascular permeability.J. Cell Sci. 2008; 121: 2115-2122Crossref PubMed Scopus (651) Google Scholar). Stimuli such as high concentrations of histamine, thrombin, or growth factors may increase endothelial cell permeability through an effect on cell contractility mediated by phosphorylation of myosin light chain and activation of p21-activated kinase (PAK) (Stockton et al., 2004Stockton R.A. Schaefer E. Schwartz M.A. p21-activated kinase regulates endothelial permeability through modulation of contractility.J. Biol. Chem. 2004; 279: 46621-46630Crossref PubMed Scopus (126) Google Scholar). However, increased permeability in vitro and in vivo could also be observed in the presence of more subtle changes in AJ organization. Histamine, tumor necrosis factor, platelet activating factor, and vascular endothelial growth factor (VEGF) induce tyrosine phosphorylation of VE-cadherin, β-catenin, and p120. This phosphorylation of AJ proteins parallels increases in permeability in cell culture systems (Dejana et al., 2008Dejana E. Orsenigo F. Lampugnani M.G. The role of adherens junctions and VE-cadherin in the control of vascular permeability.J. Cell Sci. 2008; 121: 2115-2122Crossref PubMed Scopus (651) Google Scholar). Src is likely implicated in phosphorylation of AJs as it is directly associated with the VE-cadherin/catenin complex, and src gene inactivation or treatment with inhibitors blocks VEGF-induced VE-cadherin phosphorylation (Weis et al., 2004Weis S. Shintani S. Weber A. Kirchmair R. Wood M. Cravens A. McSharry H. Iwakura A. Yoon Y.S. Himes N. et al.Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction.J. Clin. Invest. 2004; 113: 885-894Crossref PubMed Scopus (281) Google Scholar). VE-cadherin may also be phosphorylated through inhibition of associated phosphatases. The phosphatase VE-PTP is of particular interest as it is endothelial-specific and associates with VE-cadherin. Inactivation of the VE-PTP gene leads to a phenotype comparable to that of VE-cadherin null embryos. This suggests that vessels cannot form correctly if VE-cadherin is constantly phosphorylated (Baumer et al., 2006Baumer S. Keller L. Holtmann A. Funke R. August B. Gamp A. Wolburg H. Wolburg-Buchholz K. Deutsch U. Vestweber D. Vascular endothelial cell-specific phosphotyrosine phosphatase (VE-PTP) activity is required for blood vessel development.Blood. 2006; 107: 4754-4762Crossref PubMed Scopus (112) Google Scholar). Other phosphatases such as Dep-1, PTP-μ, and SHP2 may also associate with VE-cadherin and, directly or indirectly, decrease phosphorylation and increase barrier function (Dejana et al., 2008Dejana E. Orsenigo F. Lampugnani M.G. The role of adherens junctions and VE-cadherin in the control of vascular permeability.J. Cell Sci. 2008; 121: 2115-2122Crossref PubMed Scopus (651) Google Scholar). There are also other kinases besides src that may be associated with the VE-cadherin/catenin complex and modulate permeability. This includes Csk, which binds to phosphorylated VE-cadherin and inhibits Src (Vestweber, 2008Vestweber D. VE-cadherin: the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 223-232Crossref PubMed Scopus (464) Google Scholar). Permeability may also be regulated by VE-cadherin internalization. VE-cadherin can be internalized in a clathrin-dependent manner. Binding of p120 to VE-cadherin prevents internalization, suggesting that p120 may act as a plasma membrane retention signal. Therefore, any condition that reduces VE-cadherin affinity for p120, such as tyrosine phosphorylation, may increase its internalization. A recent report found that VEGF disrupts endothelial barrier function by activating src, which in turn phosphorylates Vav2, a guanine exchange factor for Rac. Activated Rac induces VE-cadherin phosphorylation in Ser665. This process induces the recruitment of β-arrestin 2, which promotes clathrin dependent VE-cadherin internalization. In this scenario, phosphorylation of VE-cadherin in Ser665 together with tyrosine would be the crucial step for increase in permeability (Gavard and Gutkind, 2006Gavard J. Gutkind J.S. VEGF controls endothelial-cell permeability by promoting the β-arrestin-dependent endocytosis of VE-cadherin.Nat. Cell Biol. 2006; 8: 1223-1234Crossref PubMed Scopus (732) Google Scholar). Importantly, the same authors found that angiopoietin 1, which in many conditions reduces vascular permeability, induces src trapping by mDia, reducing its activity at AJs (Gavard et al., 2008Gavard J. Patel V. Gutkind J.S. Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia.Dev. Cell. 2008; 14: 25-36Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar). Another pathway that may induce vascular permeability is VE-cadherin cleavage. The VE-cadherin protein is particularly susceptible to enzymatic proteolysis. Exposure to elastase, Adam-10, and others induces digestion of VE-cadherin in cultured cells (for review see Dejana et al., 2008Dejana E. Orsenigo F. Lampugnani M.G. The role of adherens junctions and VE-cadherin in the control of vascular permeability.J. Cell Sci. 2008; 121: 2115-2122Crossref PubMed Scopus (651) Google Scholar). Leukocytes and tumor cells can release high amounts of these enzymes, promoting VE-cadherin cleavage and thus increasing cell extravasation and vascular leakage. Permeability control may also be achieved through up or downregulation of VE-cadherin expression. Analysis of the VE-cadherin promoter showed different binding sites for several transcription factors known to act in endothelial cell differentiation. Among these TAL-1, Ets-1, ERG, or hypoxia inducible factors were found to effectively upregulate VE-cadherin (Birdsey et al., 2008Birdsey G.M. Dryden N.H. Amsellem V. Gebhardt F. Sahnan K. Haskard D.O. Dejana E. Mason J.C. Randi A.M. Transcription factor Erg regulates angiogenesis and endothelial apoptosis through VE-cadherin.Blood. 2008; 111: 3498-3506Crossref PubMed Scopus (180) Google Scholar, Deleuze et al., 2007Deleuze V. Chalhoub E. El-Hajj R. Dohet C. Le Clech M. Couraud P.O. Huber P. Mathieu D. TAL-1/SCL and its partners E47 and LMO2 up-regulate VE-cadherin expression in endothelial cells.Mol. Cell. Biol. 2007; 27: 2687-2697Crossref PubMed Scopus (65) Google Scholar). Although VE-cadherin is present in high molecular number on cultured endothelial cell" @default.
• W2010045296 created "2016-06-24" @default.
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• W2010045296 date "2009-02-01" @default.
• W2010045296 modified "2023-10-18" @default.
• W2010045296 title "The Control of Vascular Integrity by Endothelial Cell Junctions: Molecular Basis and Pathological Implications" @default.
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