TNF-induced endothelial barrier disruption: beyond actin and Rho

Summary

The decrease of endothelial barrier function is central to the long-term inflammatory response. A pathological alteration of the ability of endothelial cells to modulate the passage of cells and solutes across the vessel underlies the development of inflammatory diseases such as atherosclerosis and multiple sclerosis. The inflammatory cytokine tumour necrosis factor (TNF) mediates changes in the barrier properties of the endothelium. TNF activates different Rho GTPases, increases filamentous actin and remodels endothelial cell morphology. However, inhibition of actin-mediated remodelling is insufficient to prevent endothelial barrier disruption in response to TNF, suggesting that additional molecular mechanisms are involved. Here we discuss, first, the pivotal role of Rac-mediated generation of reactive oxygen species (ROS) to regulate the integrity of endothelial cell-cell junctions and, second, the ability of endothelial adhesion receptors such as ICAM-1, VCAM-1 and PECAM-1, involved in leukocyte transendothelial migration, to control endothelial permeability to small molecules, often through ROS generation. These adhesion receptors regulate endothelial barrier function in ways both dependent on and independent of their engagement by immune cells, and orchestrate the crosstalk between leukocyte transendothelial migration and endothelial permeability during inflammation.

Keywords

Endothelial barrier function - permeability - adhesion - transendothelial migration - Rho - Rac - Cdc42 - ROCK - reactive oxygen species - Src - Fyn - actin - VE-cadherin - ICAM-1 - VCAM-1 - JAM - PECAM-1 - SHP phosphatases - metalloproteases

^* Equal contribution.

• References

• 1 Medzhitov R. Inflammation 2010: new adventures of an old flame. Cell 2010; 140: 771-776.
• 2 Madge LA, Pober JS. TNF signalling in vascular endothelial cells. Exp Mol Path-ol 2001; 70: 317-325.
• 3 Ruddle N H.. Tumor necrosis factor (TNF-alpha) and lymphotoxin (TNF-beta). Curr Opin Immunol 1992; 04: 327-332.
• 4 Bradley JR. TNF-mediated inflammatory disease. J Pathol 2008; 214: 149-160.
• 5 Scheller J. et al. ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol 2011; 32: 380-387.
• 6 Black RA. et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 1997; 385: 729-733.
• 7 Cabal-Hierro L, Lazo PS. Signal transduction by tumor necrosis factor receptors. Cell Signal 2012; 24: 1297-1305.
• 8 Waters JP. et al. Tumour necrosis factor and cancer. J Pathol 2013; 230: 241-248.
• 9 Waters JP. et al. Tumour necrosis factor in infectious disease. J Pathol 2013; 230: 132-147.
• 10 Chu WM. Tumor necrosis factor. Cancer Lett 2013; 328: 222-225.
• 11 Vallabhapurapu S, Karin M. Regulation and function of NF-kappaB transcription factors in the immune system. Ann Rev Immunol 2009; 27: 693-733.
• 12 Brenner DA. et al. Prolonged activation of jun and collagenase genes by tumour necrosis factor-alpha. Nature 1989; 337: 661-663.
• 13 Vandenabeele P. et al. The role of the kinases RIP1 and RIP3 in TNF-induced necrosis. Sci Signal 2010; 03: re4.
• 14 Ridley AJ. Rho family proteins: coordinating cell responses. Trends Cell Biol 2001; 11: 471-477.
• 15 Wennerberg K, Der CJ. Rho-family GTPases: it‘s not only Rac and Rho (and I like it). J Cell Sci 2004; 117: 1301-1312.
• 16 Ridley AJ. Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol 2006; 16: 522-529.
• 17 McKenzie JA, Ridley AJ. Roles of Rho/ROCK and MLCK in TNF-alpha-induced changes in endothelial morphology and permeability. J Cell Physiol 2007; 213: 221-228.
• 18 Hanna AN. et al. Tumor necrosis factor-alpha induces stress fibre formation through ceramide production: role of sphingosine kinase. Mol Biol Cell 2001; 12: 3618-3630.
• 19 Puls A. et al. Activation of the small GTPase Cdc42 by the inflammatory cytokines TNF(alpha) and IL-1, and by the Epstein-Barr virus transforming protein LMP1. J Cell Sci 1999; 112: 2983-2992.
• 20 Wojciak-Stothard B. et al. Regulation of TNF-alpha-induced reorganisation of the actin cytoskeleton and cell-cell junctions by Rho, Rac, and Cdc42 in human endothelial cells. J Cell Physiol 1998; 176: 150-165.
• 21 Kant S.. et al. TNF-stimulated MAP kinase activation mediated by a Rho family GTPase signalling pathway. Genes Dev 2011; 25: 2069-2078.
• 22 Fernandez-Martin L. et al. Crosstalk between reticular adherens junctions and platelet endothelial cell adhesion molecule-1 regulates endothelial barrier function. Arterioscl Thromb Vasc Biol 2012; 32: e90-e102.
• 23 Hocking DC. et al. Mechanisms of pulmonary edema induced by tumor necrosis factor-alpha. Circulation Res 1990; 67: 68-77.
• 24 Stolpen AH. et al. Recombinant tumor necrosis factor and immune interferon act singly and in combination to reorganize human vascular endothelial cell monolayers. Am J Pathol 1986; 123: 16-24.
• 25 Deli MA. et al. Exposure of tumor necrosis factor-alpha to luminal membrane of bovine brain capillary endothelial cells cocultured with astrocytes induces a delayed increase of permeability and cytoplasmic stress fibre formation of actin. J Neurosci Res 1995; 41: 717-726.
• 26 Kimura K. et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 1996; 273: 245-248.
• 27 Watanabe N. et al. Cooperation between mDia1 and ROCK in Rho-induced actin reorganisation. Nature Cell Biol 1999; 01: 136-143.
• 28 Chrzanowska-Wodnicka M, Burridge K. Rho-stimulated contractility drives the formation of stress fibres and focal adhesions. J Cell Biol 1996; 133: 1403-1415.
• 29 Amano M. et al. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J Biol Chem 1996; 271: 20246-20249.
• 30 Mong PY. et al. Activation of Rho kinase by TNF-alpha is required for JNK activation in human pulmonary microvascular endothelial cells. J Immunol 2008; 180: 550-558.
• 31 Campos SB. et al. Cytokine-induced F-actin reorganisation in endothelial cells involves RhoA activation. Am J Physiol Renal Physiol 2009; 296: F487-495.
• 32 Schlegel N, Waschke J. Impaired cAMP and Rac 1 signalling contribute to TNF-alpha-induced endothelial barrier breakdown in microvascular endothelium. Microcirculation 2009; 16: 521-533.
• 33 Mong PY, Wang Q. Activation of Rho kinase isoforms in lung endothelial cells during inflammation. J Immunol 2009; 182: 2385-2394.
• 34 Millan J. et al. Adherens junctions connect stress fibres between adjacent endothelial cells. BMC Biol 2010; 08: 11.
• 35 Dejana E. Endothelial cell-cell junctions: happy together. Nat Rev Mol Cell Biol 2004; 05: 261-270.
• 36 Huveneers S. et al. Vinculin associates with endothelial VE-cadherin junctions to control force-dependent remodelling. J Cell Biol 2012; 196: 641-652.
• 37 Naikawadi RP. et al. A critical role for phosphatidylinositol (3,4,5)-trisphosphate-dependent Rac exchanger 1 in endothelial junction disruption and vascular hyperpermeability. Circulation Res 2012; 11: 1517-1527.
• 38 Shao M. et al. Caveolin-1 regulates Rac1 activation and rat pulmonary micro-vascular endothelial hyperpermeability induced by TNF-alpha. PLoS ONE 2013; 08: e55213.
• 39 Van Rijssel J. et al. The Rho-GEF Trio regulates a novel pro-inflammatory pathway through the transcription factor Ets2. Biol Open 2013; 02: 569-579.
• 40 Cain RJ. et al. The PI3K p110alpha isoform regulates endothelial adherens junctions via Pyk2 and Rac1. J Cell Biol 2010; 188: 863-876.
• 41 Papakonstanti EA, Stournaras C. Tumor necrosis factor-alpha promotes survival of opossum kidney cells via Cdc42-induced phospholipase C-gamma1 activation and actin filament redistribution. Mol Biol Cell 2004; 15: 1273-1286.
• 42 Vandenbroucke E. et al. Regulation of endothelial junctional permeability. Ann NY Acad Sci 2008; 1123: 134-145.
• 43 van Nieuw Amerongen GP. et al. Involvement of Rho kinase in endothelial barrier maintenance. Arterioscl Thromb Vasc Biol 2007; 27: 2332-2339.
• 44 Wojciak-Stothard B. et al. Rho and Rac but not Cdc42 regulate endothelial cell permeability. J Cell Sci 2001; 114: 1343-1355.
• 45 Wojciak-Stothard B, Ridley AJ. Rho GTPases and the regulation of endothelial permeability. Vascul Pharmacol 2002; 39: 187-199.
• 46 Petrache I. et al. Differential effect of MLC kinase in TNF-alpha-induced endothelial cell apoptosis and barrier dysfunction. Am J Physiol Lung Cell Mol Physiol 2001; 280: L1168-1178.
• 47 Reed SC. et al. Rickettsia parkeri invasion of diverse host cells involves an Arp2/3 complex, WAVE complex and Rho-family GTPase-dependent pathway. Cell Microbiol 2012; 14: 529-545.
• 48 Bandman O. et al. Complexity of inflammatory responses in endothelial cells and vascular smooth muscle cells determined by microarray analysis. Ann NY Acad Sci 2002; 975: 77-90.
• 49 Giusti B. et al. Desmoglein-2-integrin Beta-8 interaction regulates actin assembly in endothelial cells: deregulation in systemic sclerosis. PLoS ONE 2013; 08: e68117.
• 50 Birukova AA. et al. HGF attenuates thrombin-induced endothelial permeability by Tiam1-mediated activation of the Rac pathway and by Tiam1/Rac-dependent inhibition of the Rho pathway. Faseb J 2007; 21: 2776-2786.
• 51 Di Lorenzo A. et al. eNOS derived nitric oxide regulates endothelial barrier function via VE cadherin and Rho GTPases. J Cell Sci. 2013 Epub ahead of print.
• 52 Gavard J, Gutkind JS. VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 2006; 08: 1223-1234.
• 53 Birukova AA. et al. Epac/Rap and PKA are novel mechanisms of ANP-induced Rac-mediated pulmonary endothelial barrier protection. J Cell Physiol 2008; 215: 715-724.
• 54 Konior A. et al. NADPH Oxidases in Vascular Pathology. Antioxid Redox Signal. 2013 Epub ahead of print.
• 55 Van Buul JD. et al. Expression and localisation of NOX2 and NOX4 in primary human endothelial cells. Antioxid Redox Signal 2005; 07: 308-317.
• 56 Frey RS. et al. NADPH oxidase-dependent signalling in endothelial cells: role in physiology and pathophysiology. Antioxid Redox Signal 2009; 11: 791-810.
• 57 Hordijk PL. Regulation of NADPH oxidases: the role of Rac proteins. Circulation Res 2006; 98: 453-462.
• 58 Martyn KD. et al. Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell Signal 2006; 18: 69-82.
• 59 Bedard K. et al. NOX5: from basic biology to signalling and disease. Free Radical Biol Med 2012; 52: 725-734.
• 60 Kim YS. et al. TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol Cell 2007; 26: 675-687.
• 61 Li JM. et al. Acute tumor necrosis factor alpha signalling via NADPH oxidase in microvascular endothelial cells: role of p47phox phosphorylation and binding to TRAF4. Mol Cell Biol 2005; 25: 2320-2330.
• 62 Zhao J. et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc Natl Acad Sci USA 2012; 109: 5322-5327.
• 63 Corcoran A, Cotter TG. Redox regulation of protein kinases. Febs J 2013; 280: 1944-1965.
• 64 Giannoni E, Chiarugi P. Redox Circuitries Driving Src Regulation. Antiox Redox Signal. 2013 Epub ahead of print.
• 65 Saksena S. et al. Role of Fyn and PI3K in H2O2-induced inhibition of apical Cl-/ OH- exchange activity in human intestinal epithelial cells. Biochem J 2008; 416: 99-108.
• 66 Giannoni E. et al. Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage-dependent cell growth. Mol Cell Biol 2005; 25: 6391-6403.
• 67 Kemble DJ, Sun G. Direct and specific inactivation of protein tyrosine kinases in the Src and FGFR families by reversible cysteine oxidation. Proc Natl Acad Sci USA 2009; 106: 5070-5075.
• 68 Monaghan-Benson E, Burridge K. The regulation of vascular endothelial growth factor-induced microvascular permeability requires Rac and reactive oxygen species. J Biol Chem 2009; 284: 25602-25611.
• 69 Potter MD. et al. Tyrosine phosphorylation of VE-cadherin prevents binding of p120- and beta-catenin and maintains the cellular mesenchymal state. J Biol Chem 2005; 280: 31906-31912.
• 70 Nwariaku FE. et al. Tyrosine phosphorylation of vascular endothelial cadherin and the regulation of microvascular permeability. Surgery 2002; 132: 180-185.
• 71 Angelini DJ. et al. TNF-alpha increases tyrosine phosphorylation of vascular endothelial cadherin and opens the paracellular pathway through fyn activation in human lung endothelia. Am J Physiol Lung Cell Mol Physiol 2006; 291: L1232-1245.
• 72 Ferrero E. et al. Tumor necrosis factor alpha-induced vascular leakage involves PECAM1 phosphorylation. Cancer Res 1996; 56: 3211-3215.
• 73 van Buul JD. et al. Proline-rich tyrosine kinase 2 (Pyk2) mediates vascular endothelial-cadherin-based cell-cell adhesion by regulating beta-catenin tyrosine phosphorylation. J Biol Chem 2005; 280: 21129-21136.
• 74 Schlaepfer DD. et al. Tumor necrosis factor-alpha stimulates focal adhesion kinase activity required for mitogen-activated kinase-associated interleukin 6 expression. J Biol Chem 2007; 282: 17450-17459.
• 75 Tseng WP. et al. FAK activation is required for TNF-alpha-induced IL-6 production in myoblasts. J Cell Physiol 2010; 223: 389-396.
• 76 Mon NN. et al. A role for focal adhesion kinase signalling in tumor necrosis factor-alpha-dependent matrix metalloproteinase-9 production in a cholangiocarcinoma cell line, CCKS1. Cancer Res 2006; 66: 6778-6784.
• 77 Knezevic N. et al. The G protein betagamma subunit mediates reannealing of adherens junctions to reverse endothelial permeability increase by thrombin. J Exp Med 2009; 206: 2761-2777.
• 78 Belvitch P, Dudek SM. Role of FAK in S1P-regulated endothelial permeability. Microvasc Res 2012; 83: 22-30.
• 79 Chen XL. et al. VEGF-induced vascular permeability is mediated by FAK. Develop Cell 2012; 22: 146-157.
• 80 Dikic I. et al. A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation. Nature 1996; 383: 547-550.
• 81 Matsui A. et al. Central role of calcium-dependent tyrosine kinase PYK2 in endothelial nitric oxide synthase-mediated angiogenic response and vascular function. Circulation 2007; 116: 1041-1051.
• 82 Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nature Rev Immunol 2013; 13: 159-175.
• 83 Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nature Rev Immunol 2011; 11: 762-774.
• 84 Shechter R. et al. Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nature reviews. Immunol 2013; 13: 206-218.
• 85 Pober JS. et al. Two distinct monokines, interleukin 1 and tumor necrosis factor, each independently induce biosynthesis and transient expression of the same antigen on the surface of cultured human vascular endothelial cells. J Immunol 1986; 136: 1680-1687.
• 86 Osborn L. et al. Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell 1989; 59: 1203-1211.
• 87 Shimizu Y. et al. Four molecular pathways of T cell adhesion to endothelial cells: roles of LFA-1, VCAM-1, and ELAM-1 and changes in pathway hierarchy under different activation conditions. J Cell Biol 1991; 113: 1203-1212.
• 88 Pober JS. et al. Activation of cultured human endothelial cells by recombinant lymphotoxin: comparison with tumor necrosis factor and interleukin 1 species. J Immunol 1987; 138: 3319-3324.
• 89 Liu Z. et al. Differential regulation of human and murine P-selectin expression and function in vivo. J Exp Med 2010; 207: 2975-2987.
• 90 Reglero-Real N. et al. Endothelial membrane reorganisation during leukocyte extravasation. Cell Mol Life Sci 2012; 69: 3079-3099.
• 91 Romer LH. et al. IFN-gamma and TNF-alpha induce redistribution of PECAM-1 (CD31) on human endothelial cells. J Immunol 1995; 154: 6582-6592.
• 92 Martinez-Estrada OM. et al. Opposite effects of tumor necrosis factor and soluble fibronectin on junctional adhesion molecule-A in endothelial cells. Am J Physiol Lung Cell Mol Physiol 2005; 288: L1081-1088.
• 93 Millan J. et al. Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domains. Nat Cell Biol 2006; 08: 113-123.
• 94 Carman CV. et al. Transcellular diapedesis is initiated by invasive podosomes. Immunity 2007; 26: 784-797.
• 95 Keuschnigg J. et al. The prototype endothelial marker PAL-E is a leukocyte trafficking molecule. Blood 2009; 114: 478-484.
• 96 Aranda JF. et al. MYADM controls endothelial barrier function through ERM-dependent regulation of ICAM-1 expression. Mol Biol Cell 2013; 24: 483-494.
• 97 Zhou Z. et al. TNFR1-induced NF-kappaB, but not ERK, p38MAPK or JNK activation, mediates TNF-induced ICAM-1 and VCAM-1 expression on endothelial cells. Cell Signal 2007; 19: 1238-1248.
• 98 Mackay F. et al. Tumor necrosis factor alpha (TNF-alpha)-induced cell adhesion to human endothelial cells is under dominant control of one TNF receptor type, TNF-R55. J Exp Med 1993; 177: 1277-1286.
• 99 Roebuck KA, Finnegan A. Regulation of intercellular adhesion molecule-1 (CD54) gene expression. J Leukocyte Biol 1999; 66: 876-888.
• 100 Collins T. et al. Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J 1995; 09: 899-909.
• 101 Ledebur HC, Parks TP. Transcriptional regulation of the intercellular adhesion molecule-1 gene by inflammatory cytokines in human endothelial cells. Essential roles of a variant NF-kappa B site and p65 homodimers. J Biol Chem 1995; 270: 933-943.
• 102 Shi JX. et al. MK2 posttranscriptionally regulates TNF-alpha-induced expression of ICAM-1 and IL-8 via tristetraprolin in human pulmonary micro-vascular endothelial cells. Am J Physiol Lung Cell Mol Physiol 2012; 302: L793-799.
• 103 Su X. et al. Post-transcriptional regulation of TNF-induced expression of ICAM-1 and IL-8 in human lung microvascular endothelial cells: an obligatory role for the p38 MAPK-MK2 pathway dissociated with HSP27. Biochim Biophys Acta 2008; 1783: 1623-1631.
• 104 Allingham MJ. et al. ICAM-1-mediated, Src- and Pyk2-dependent vascular endothelial cadherin tyrosine phosphorylation is required for leukocyte transendothelial migration. J Immunol 2007; 179: 4053-4064.
• 105 Wojciak-Stothard B. et al. Monocyte adhesion and spreading on human endothelial cells is dependent on Rho-regulated receptor clustering. J Cell Biol 1999; 145: 1293-1307.
• 106 Barreiro O. et al. Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J Cell Biol 2002; 157: 1233-1245.
• 107 Clark PR. et al. Increased ICAM-1 expression causes endothelial cell leakiness, cytoskeletal reorganisation and junctional alterations. J Invest Dermatol 2007; 127: 762-774.
• 108 Fehon RG. et al. Organising the cell cortex: the role of ERM proteins. Nat Rev Mol Cell Biol 2010; 11: 276-287.
• 109 Oh HM. et al. RKIKK motif in the intracellular domain is critical for spatial and dynamic organisation of ICAM-1: functional implication for the leukocyte adhesion and transmigration. Mol Biol Cell 2007; 18: 2322-2335.
• 110 Koss M. et al. Ezrin/radixin/moesin proteins are phosphorylated by TNF-alpha and modulate permeability increases in human pulmonary microvascular endothelial cells. J Immunol 2006; 176: 1218-1227.
• 111 Xiao X. et al. Intercellular adhesion molecule-1 is a regulator of blood-testis barrier function. J Cell Sci 2012; 125: 5677-5689.
• 112 Sumagin R. et al. Leukocyte rolling and adhesion both contribute to regulation of microvascular permeability to albumin via ligation of ICAM-1. Am J Physiol Cell Physiol 2011; 301: C804-813.
• 113 Sumagin R. et al. Leukocyte-endothelial cell interactions are linked to vascular permeability via ICAM-1-mediated signalling. Am J Physiol Heart Circ Physiol 2008; 295: H969-H977.
• 114 Thompson PW. et al. Intercellular adhesion molecule (ICAM)-1, but not ICAM-2, activates RhoA and stimulates c-fos and rhoA transcription in endothelial cells. J Immunol 2002; 169: 1007-1013.
• 115 Turowski P. et al. Phosphorylation of vascular endothelial cadherin controls lymphocyte emigration. J Cell Sci 2008; 121: 29-37.
• 116 van Rijssel J. et al. The Rho-guanine nucleotide exchange factor Trio controls leukocyte transendothelial migration by promoting docking structure formation. Mol Biol Cell 2012; 23: 2831-2844.
• 117 Durieu-Trautmann O. et al. Intercellular adhesion molecule 1 activation induces tyrosine phosphorylation of the cytoskeleton-associated protein cortactin in brain microvessel endothelial cells. J Biol Chem 1994; 269: 12536-12540.
• 118 Wolf SI. et al. Agonistic anti-ICAM-1 antibodies in scleroderma: activation of endothelial pro-inflammatory cascades. Vasc Pharmacol 2013; 59: 19-26.
• 119 Etienne-Manneville S. et al. ICAM-1-coupled cytoskeletal rearrangements and transendothelial lymphocyte migration involve intracellular calcium signalling in brain endothelial cell lines. J Immunol 2000; 165: 3375-3383.
• 120 Gong P. et al. TLR4 signalling is coupled to SRC family kinase activation, tyro-sine phosphorylation of zonula adherens proteins, and opening of the paracellular pathway in human lung microvascular endothelia. J Biol Chem 2008; 283: 13437-13449.
• 121 Wallez Y. et al. Src kinase phosphorylates vascular endothelial-cadherin in response to vascular endothelial growth factor: identification of tyrosine 685 as the unique target site. Oncogene 2007; 26: 1067-1077.
• 122 Tilghman RW, Hoover RL. The Src-cortactin pathway is required for clustering of E-selectin and ICAM-1 in endothelial cells. Faseb J 2002; 16: 1257-1259.
• 123 Wessel F. et al. Leukocyte extravasation and vascular permeability are each controlled in vivo by different tyrosine residues of VE-cadherin. Nature Immunol 2014; 15: 223-230.
• 124 Etienne S. et al. ICAM-1 signalling pathways associated with Rho activation in microvascular brain endothelial cells. J Immunol 1998; 161: 5755-5761.
• 125 Adamson P. et al. Lymphocyte migration through brain endothelial cell mono-layers involves signalling through endothelial ICAM-1 via a rho-dependent pathway. J Immunol 1999; 162: 2964-2973.
• 126 Carman CV, Springer TA. A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J Cell Biol 2004; 167: 377-388.
• 127 Minshall RD. et al. Endothelial cell-surface gp60 activates vesicle formation and trafficking via G(i)-coupled Src kinase signalling pathway. J Cell Biol 2000; 150: 1057-1070.
• 128 Hu G. et al. Intercellular adhesion molecule-1-dependent neutrophil adhesion to endothelial cells induces caveolae-mediated pulmonary vascular hyperpermeability. Circulation Res 2008; 102: e120-131.
• 129 Sun Y. et al. Phosphorylation of caveolin-1 regulates oxidant-induced pulmonary vascular permeability via paracellular and transcellular pathways. Circulation Res 2009; 105: 676-685.
• 130 Neish AS. et al. Functional analysis of the human vascular cell adhesion molecule 1 promoter. J Exp Med 1992; 176: 1583-1593.
• 131 Iademarco MF. et al. Characterisation of the promoter for vascular cell adhesion molecule-1 (VCAM-1). J Biol Chem 1992; 267: 16323-16329.
• 132 van Wetering S. et al. VCAM-1-mediated Rac signalling controls endothelial cell-cell contacts and leukocyte transmigration. Am J Physiol Cell Physiol 2003; 285: C343-352.
• 133 van Buul JD. et al. Migration of human hematopoietic progenitor cells across bone marrow endothelium is regulated by vascular endothelial cadherin. J Immunol 2002; 168: 588-596.
• 134 van Buul JD. et al. ICAM-1 clustering on endothelial cells recruits VCAM-1. J Biomed Biotechnol 2010; 2010: 120328.
• 135 Barreiro O. et al. Endothelial adhesion receptors are recruited to adherent leukocytes by inclusion in preformed tetraspanin nanoplatforms. J Cell Biol 2008; 183: 527-542.
• 136 van Buul JD. et al. RhoG regulates endothelial apical cup assembly downstream from ICAM1 engagement and is involved in leukocyte trans-endothelial migration. J Cell Biol 2007; 178: 1279-1293.
• 137 van Wetering S. et al. Reactive oxygen species mediate Rac-induced loss of cell-cell adhesion in primary human endothelial cells. J Cell Sci 2002; 115: 1837-1846.
• 138 Vockel M, Vestweber D. How T cells trigger the dissociation of the endothelial receptor phosphatase VE-PTP from VE-cadherin. Blood 2013; 122: 2512-2522.
• 139 Nawroth R. et al. VE-PTP and VE-cadherin ectodomains interact to facilitate regulation of phosphorylation and cell contacts. Embo J 2002; 21: 4885-4895.
• 140 Wolburg H. et al. Diapedesis of mononuclear cells across cerebral venules during experimental autoimmune encephalomyelitis leaves tight junctions intact. Acta Neuropathol 2005; 109: 181-190.
• 141 Page-McCaw A. et al. Matrix metalloproteinases and the regulation of tissue remodelling. Nature Rev Mol Cell Biol 2007; 08: 221-233.
• 142 Deem TL, Cook-Mills JM. Vascular cell adhesion molecule 1 (VCAM-1) activation of endothelial cell matrix metalloproteinases: role of reactive oxygen species. Blood 2004; 104: 2385-2393.
• 143 Moll T. et al. In vitro degradation of endothelial catenins by a neutrophil pro-tease. J Cell Biol 1998; 140: 403-407.
• 144 Dhawan S. et al. HIV-1 infection alters monocyte interactions with human microvascular endothelial cells. J Immunol 1995; 154: 422-432.
• 145 Cook-Mills JM. et al. Vascular cell adhesion molecule-1 expression and signalling during disease: regulation by reactive oxygen species and antioxidants. Antiox Redox Signal 2011; 15: 1607-1638.
• 146 Lessner SM, Galis ZS. Matrix metalloproteinases and vascular endotheliummononuclear cell close encounters. Trends Cardiovasc Med 2004; 14: 105-111.
• 147 Sidibe A. et al. Soluble VE-cadherin in rheumatoid arthritis patients correlates with disease activity: evidence for tumor necrosis factor alpha-induced VEcadherin cleavage. Arthritis Reum 2012; 64: 77-87.
• 148 Weber C. et al. The role of junctional adhesion molecules in vascular inflammation. Nat Rev Immunol 2007; 07: 467-477.
• 149 Ebnet K. et al. Regulation of epithelial and endothelial junctions by PAR proteins. Front Biosci 2008; 13: 6520-6536.
• 150 Ebnet K. et al. Junctional adhesion molecule interacts with the PDZ domain-containing proteins AF-6 and ZO-1. J Biol Chem 2000; 275: 27979-27988.
• 151 Bazzoni G. et al. Interaction of junctional adhesion molecule with the tight junction components ZO-1, cingulin, and occludin. J Biol Chem 2000; 275: 20520-20526.
• 152 Ebnet K. et al. The junctional adhesion molecule (JAM) family members JAM-2 and JAM-3 associate with the cell polarity protein PAR-3: a possible role for JAMs in endothelial cell polarity. J Cell Sci 2003; 116: 3879-3891.
• 153 Itoh M. et al. Junctional adhesion molecule (JAM) binds to PAR-3: a possible mechanism for the recruitment of PAR-3 to tight junctions. J Cell Biol 2001; 154: 491-497.
• 154 Ostermann G. et al. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol 2002; 03: 151-158.
• 155 Santoso S. et al. The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1. J Exp Med 2002; 196: 679-691.
• 156 Cunningham SA. et al. JAM2 interacts with alpha4beta1. Facilitation by JAM3. J Biol Chem 2002; 277: 27589-27592.
• 157 Arrate MP. et al. Cloning of human junctional adhesion molecule 3 (JAM3) and its identification as the JAM2 counter-receptor. J Biol Chem 2001; 276: 45826-45832.
• 158 Vetrano S. et al. Unique role of junctional adhesion molecule-a in maintaining mucosal homeostasis in inflammatory bowel disease. Gastroenterology 2008; 135: 173-184.
• 159 Mandell KJ. et al. Involvement of the junctional adhesion molecule-1 (JAM1) homodimer interface in regulation of epithelial barrier function. J Biol Chem 2004; 279: 16254-16262.
• 160 Liu Y. et al. Human junction adhesion molecule regulates tight junction resealing in epithelia. J Cell Sci 2000; 113: 2363-2374.
• 161 Li X. et al. JAM-C induces endothelial cell permeability through its association and regulation of {beta}3 integrins. Arterioscl Thromb Vasc Biol 2009; 29: 1200-1206.
• 162 Orlova VV. et al. Junctional adhesion molecule-C regulates vascular endothelial permeability by modulating VE-cadherin-mediated cell-cell contacts. J Exp Med 2006; 203: 2703-2714.
• 163 Sircar M. et al. Neutrophil transmigration under shear flow conditions in vitro is junctional adhesion molecule-C independent. J Immunol 2007; 178: 5879-5887.
• 164 Ozaki H. et al. Cutting edge: combined treatment of TNF-alpha and IFN-gamma causes redistribution of junctional adhesion molecule in human endothelial cells. J Immunol 1999; 163: 553-557.
• 165 Ueki T. et al. Expression of junctional adhesion molecules on the human lymphatic endothelium. Microvasc Res 2008; 75: 269-278.
• 166 Shaw SK. et al. Reduced expression of junctional adhesion molecule and platelet/endothelial cell adhesion molecule-1 (CD31) at human vascular endothelial junctions by cytokines tumor necrosis factor-alpha plus interferon-gamma Does not reduce leukocyte transmigration under flow. Am J Pathol 2001; 159: 2281-2291.
• 167 Liang TW. et al. Vascular endothelial-junctional adhesion molecule (VE-JAM)/JAM 2 interacts with T, NK, and dendritic cells through JAM 3. J Immunol 2002; 168: 1618-1626.
• 168 Mamdouh Z. et al. Targeted recycling of PECAM from endothelial surface-connected compartments during diapedesis. Nature 2003; 421: 748-753.
• 169 Biswas P. et al. PECAM-1 affects GSK-3beta-mediated beta-catenin phosphorylation and degradation. Am J Pathol 2006; 169: 314-324.
• 170 Graesser D. et al. Altered vascular permeability and early onset of experimental autoimmune encephalomyelitis in PECAM-1-deficient mice. J Clin Invest 2002; 109: 383-392.
• 171 Privratsky JR. et al. Relative contribution of PECAM-1 adhesion and signalling to the maintenance of vascular integrity. J Cell Sci 2011; 124: 1477-1485.
• 172 Cao MY. et al. Regulation of mouse PECAM-1 tyrosine phosphorylation by the Src and Csk families of protein-tyrosine kinases. J Biol Chem 1998; 273: 15765-15772.
• 173 Lu TT. et al. Platelet endothelial cell adhesion molecule-1 is phosphorylatable by c-Src, binds Src-Src homology 2 domain, and exhibits immunoreceptor tyrosine-based activation motif-like properties. J Biol Chem 1997; 272: 14442-14446.
• 174 Kogata N. et al. Identification of Fer tyrosine kinase localized on microtubules as a platelet endothelial cell adhesion molecule-1 phosphorylating kinase in vascular endothelial cells. Mol Biol Cell 2003; 14: 3553-3564.
• 175 Bird IN. et al. Homophilic PECAM-1(CD31) interactions prevent endothelial cell apoptosis but do not support cell spreading or migration. J Cell Sci 1999; 112: 1989-1997.
• 176 Ilan N. et al. PECAM-1 (CD31) functions as a reservoir for and a modulator of tyrosine-phosphorylated beta-catenin. J Cell Sci 1999; 112: 3005-3014.
• 177 Ilan N. et al. Platelet-endothelial cell adhesion molecule-1 (CD31), a scaffolding molecule for selected catenin family members whose binding is mediated by different tyrosine and serine/threonine phosphorylation. J Biol Chem 2000; 275: 21435-21443.
• 178 Ukropec JA. et al. SHP2 association with VE-cadherin complexes in human endothelial cells is regulated by thrombin. J Biol Chem 2000; 275: 5983-5986.
• 179 Timmerman I. et al. The tyrosine phosphatase SHP2 regulates recovery of endothelial adherens junctions through control of beta-catenin phosphorylation. Mol Biol Cell 2012; 23: 4212-4225.
• 180 Grinnell KL. et al. Role of protein tyrosine phosphatase SHP2 in barrier function of pulmonary endothelium. Am J Physiol. Lung Cell Mol Physiol 2010; 298: L361-370.
• 181 Henshall TL. et al. Src homology 2 domain-containing protein-tyrosine phosphatases, SHP-1 and SHP-2, are required for platelet endothelial cell adhesion molecule-1/CD31-mediated inhibitory signalling. J Immunol 2001; 166: 3098-3106.
• 182 Mamdouh Z. et al. Transcellular migration of leukocytes is mediated by the endothelial lateral border recycling compartment. J Exp Med 2009; 206: 2795-2808.
• 183 You M. et al. Modulation of the nuclear factor kappa B pathway by Shp-2 tyro-sine phosphatase in mediating the induction of interleukin (IL)-6 by IL-1 or tumor necrosis factor. J Exp Med 2001; 101-110.
• 184 Daigle I. et al. Death receptors bind SHP-1 and block cytokine-induced anti-apoptotic signalling in neutrophils. Nature Med 2002; 08: 61-67.
• 185 Lerner-Marmarosh N. et al. Inhibition of tumor necrosis factor-[alpha]-induced SHP-2 phosphatase activity by shear stress: a mechanism to reduce endothelial inflammation. Arterioscl Thromb Vasc Biol 2003; 23: 1775-1781.
• 186 Koch E. et al. The endothelial tyrosine phosphatase SHP-1 plays an important role for vascular haemostasis in TNFalpha -induced inflammation in vivo. Mediators Inflamm 2013; 2013: 279781.
• 187 Nakagami H. et al. Tumor necrosis factor-alpha inhibits growth factor-mediated cell proliferation through SHP-1 activation in endothelial cells. Arterioscl Thromb Vasc Biol 2002; 22: 238-242.
• 188 le Duc Q. et al. Vinculin potentiates E-cadherin mechanosensing and is recruited to actin-anchored sites within adherens junctions in a myosin II-dependent manner. J Cell Biol 2010; 189: 1107-1115.