Angiogenesis pp 187-201 | Cite as

Structure and Functional Role of Endothelial Cell-to-Cell Junctions

  • Pilar Navarro
  • Maria Grazia Lampugnani
  • Elisabetta Dejana
Part of the NATO ASI Series book series (NSSA, volume 298)


Endothelial cell junctions are complex structures formed by transmembrane adhesive molecules linked to a network of cytoplasmic/cytoskeletal proteins. These structures have some features and components in common with epithelial cells but also some which are specific for the endothelium. During angiogenesis, endothelial cells need first to dissociate from neighbouring cells and invade the underlying tissues. Indirect evidence suggests that vascular growth factor(s), besides inducing endothelial cell proliferation, could also change endothelial junction organization and strength. After the first sprouting the new vascular structures get organized in a more complex network. At this stage, molecules at junctions are required for endothelial cell-to-cell anchorage and for vascular remodelling. These structures are important not only for maintaining adhesion between endothelial cells and, as a consequence, for the control of vascular permeability, but also for intracellular signal transduction. The exact pathways of signalling through cell-to-cell contacts are still obscure but seem to require the release of intracellular molecules from the junctional complex and their translocation to the cytoplasm and/or the nucleus.


Tight Junction Intercellular Junction Vascular Endothelial Cell Growth Factor Cytoplasmic Component Adenomatous Polyposis Coli Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Aberle, H., Schwartz, H., and Kemler, R., 1996, Cadherin-catenin complex: protein interactions and their implications for Cadherin functions, J. Cell. Biochem. 61: 514–523.PubMedCrossRefGoogle Scholar
  2. Anderson, J. M., Stevenson, B. R., Jesaitis, L.A., Goodenough, D.A., and Mooseker, M.S., 1988, Characterization of ZO-1, a protein component of the tight junction from mouse liver and Madin-darby canine kidney cells, J. Cell Biol 106: 1141–1149.PubMedCrossRefGoogle Scholar
  3. Anderson, J.M. and Van Itallie C.M., 1995, Tight junctions and the molecular basis for regulation of paracellular permeability, Am. J. Physiol. 269: G467–G475.Google Scholar
  4. Balda, M.S., Anderson, J.M., and Matter, K., 1996, The SH3 domain of the tight junction protein ZO-1 binds to a srine protein kinase that phosphorylates a region C-terminal to this domain, FEBS Lett. 399: 326–332.PubMedCrossRefGoogle Scholar
  5. Balda, M.S. and Anderson, J.M., 1993, Two classes of tight junctions are revealed by ZO-1 isoforms, Am. J. Phys. 264: C918–C924.Google Scholar
  6. Balsamo, J., Leung, T.C., Ernst, H., Zanin, M. K. B., Hoffman, S., Lilien, J., 1996, Regulated binding of a PTP IB-like phosphatase to N-cadherin: control of cadherin-mediated adhesion by dephosphorylation of b-catenin, J. Cell Biol. 134: 801–813.PubMedCrossRefGoogle Scholar
  7. Barth, A. I. M., Pollack, A. L., Altschuler, Y., Mostov, K. E., and Nelson, W. J., 1997, NH2-terminal deletion of b-catenin results in stable colocalization of mutant b-catenin with adenomatous polyposis coli protein and altered MDCK cell adhesion, J. Cell Biol. 136: 693–706.PubMedCrossRefGoogle Scholar
  8. Bavisotto, L. M., Schwartz, S. M., and Heinmark, R. L., 1990, Modulation of Ca2+-dependent intercellular adhesion in bovine aortic and human umbilical vein endothelial cells by heparin-binding growth factors, J. Cell. Physiol 143: 39–51.PubMedCrossRefGoogle Scholar
  9. Beherens, J., von Kries, J. P., Kuhl, M., Bruhn, L., Wedlich, D., Grosschedl, R., and Birchmeier, W., 1996, Functional interaction of b-catenin with the transcription factor LEF-1, Nature 382: 638–642.CrossRefGoogle Scholar
  10. Braga, V. M. M., Machesky, L., Hall, A. and Hotchin, N. A., The small GTPases Rho and Rac are required for the establishment of cadherin-dependent cell-cell contacts. J. Cell Biol. in press.Google Scholar
  11. Breier, G., Breviario, F., Caveda, L., Berthier, R., Schnurch, H., Gotsch, U., Vestweber, D., Risau, W., and Dejana, E., 1996, Molecular cloning and expression of murine vascular encothelial Cadherin in early stage development of cardiovascular system, Blood 87: 630–641.PubMedGoogle Scholar
  12. Brunner, E., Peter, O., Schweizer, L., and Basier, K., 1997, Pangolin encodes a Lef-1 homologue that acts downstream of Armadillo to transduce the Wingless signal in Drosophila, Nature 385: 829–833.PubMedCrossRefGoogle Scholar
  13. Caveda, L., Martin-Padura, I., Navarro, P., Breviario, F., Corada, M., Gulino, D., Lampugnani, M. G., and Dejana, E., 1996, Inhibition of cultured cell growth by vascular endothelial Cadherin (cadherin-5/VE-cadherin), J. Clin. Invest. 98: 886–893.PubMedCrossRefGoogle Scholar
  14. Citi, S., Sabanay, H., Jakes, R., Geiger, B., and Kendrick-Jones, J., 1988, Cingulin, a new peripheral component of tight junctions, Nature 333: 272–276.PubMedCrossRefGoogle Scholar
  15. Connolly, D. T., Heuvelman, D. M., Nelson, R., Olander, J. V., Eppley, B. L., Delfino, J. J., Siegel, N. R., Leimgruber, R. M., and Feder, J., 1989, Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis, J. Clin. Invest. 84: 1470–1478.PubMedCrossRefGoogle Scholar
  16. Daniel, J. M., and Reynolds, A. B., 1995, The tyrosine kinase substrate p120 cas binds directly to E-cadherin but not to the adenomatous polyposis coli protein or a-catenin, Mol. Cell. Biol. 15:4819–4824.PubMedGoogle Scholar
  17. Dehouck, B., Dehouck, M. P., Fruchart, J. C., Cecchelli, R., 1994, Upregulation of the low density lipoprotein receptor at the blood-brain barrier: intercommunictaions between brain capillary endothelial cells and astrocytes, J. Cell Biol. 126: 465–473.PubMedCrossRefGoogle Scholar
  18. Dejana, E., Corada, M., Lampugnani, M. G., 1995, Endothelial cell-to-cell junctions, FASEB J. 9:910–918.PubMedGoogle Scholar
  19. Dejana, E., 1996, Endothelial cell-cell adherens junctions: implications in the control of vascular permeability and angiogenesis, Clin. Invest. 98: 1949–1953CrossRefGoogle Scholar
  20. Fanning, A., Jameson, B. T., Anderson, J. M., 1996, Molecular interactions among the tight junction proteins ZO-1, ZO-2 and occludin, Mol. Biol. Cell 7: 607aGoogle Scholar
  21. Fuchs, M., Muller, T., Lerch, M. M., Ullrich, A., 1996, Association of human protein-tyrosine phosphatase k with members of the Armadillo family, J. Biol. Chem. 271: 16712–16719.PubMedCrossRefGoogle Scholar
  22. Furuse, M., Hirase, T., Itoh, M., Nagafuchi, A., Yonemura, S., Tsukita, S., Tsukita, Sh., 1993, Occludin: a novel integral membrane protein localizing at tight junctions, J. Cell Biol. 123: 1777–1788.PubMedCrossRefGoogle Scholar
  23. Furuse, M., Itoh, M., Hirase, T., Nagafuchi, A., Yonemura, S., Tsukita, S., Tsukita Sh., 1994, Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions, J. Cell Biol. 127: 1617–1626.PubMedCrossRefGoogle Scholar
  24. Gardner, T. W., Lesher, T., Khin, S., Vu, C., Barber, A. J., and Brennan, W. A., 1996, Histamine reduces ZO-1 tight-junction protein expresssion in cultured retinal microvascular endothelial cells, Biochem. J. 320: 717–721.PubMedGoogle Scholar
  25. Gottardi, C. J., Arpin, M., Fanning, A. S., Louvard, D., 1996, The junction-associated protein, zonula occludens-1, localizes to the nucleus before the maturation and during he remodeling of cell-cell contacts, Proc. Natl. Acad. Sci. USA, 93: 10779–10784.PubMedCrossRefGoogle Scholar
  26. Gumbiner, B., Lowenkopf, T., and Apatira, D., 1991, Identification of a 160-kDa polypeptide that binds to the tight junction protein ZO-1, Proc. Natl. Acad. Sci. USA, 88: 3460–3464.PubMedCrossRefGoogle Scholar
  27. Gumbiner, B. M., 1996, Cell adhesion: the molecular basis of tissue architecture and morphogenesis, Cell 84: 345–357.PubMedCrossRefGoogle Scholar
  28. Heimark, R. L. and Schwartz, S. M., 1985, The role of the membrane-membrane interactions in the regulation of endothelial cell growth, J. Cell Biol. 100: 1934–1940.PubMedCrossRefGoogle Scholar
  29. Hinck, L., Näthke, I.S., Papkoff, J. and Nelson, J., 1994, Beta-catenin: a common target for the regulation of cell adhesion by Wnt-1 and Src signaling pathways, TIBS 19: 538–542.PubMedGoogle Scholar
  30. Hoschuetzky, H., Aberle, H., and Kemler, R., 1994, Beta-catenin mediates the interaction of the cadherin-catenin complex with epidermal growth factor receptor, J. Cell Biol. 127: 1375–1380.PubMedCrossRefGoogle Scholar
  31. Howarth, A.G., Hughes, M. R., and Stevenson, B. R., 1992, Detection of the tight junction-associated protein ZO-1 in astrocytes and other nonepithelial cell types, Am. J. Physiol. 262: C461–C469.Google Scholar
  32. Huber, P., Dalmon, J., Engiles, J., Breviario, F., Gory, S., Buchberg, A. M., and Dejana, E., 1996, Genomic structure and chromosomal mapping of the mouse VE-cadherin gene (Cdh5), Genomics 32:21–28.PubMedCrossRefGoogle Scholar
  33. Hulsken, J., Behrens, J., and Birchmeier, W., 1994, Tumor-suppressor gene products in cell contacts: the Cadherin-APC-armadillo connection, Curr. Opin. Cell. Biol. 6: 711–716.PubMedCrossRefGoogle Scholar
  34. Itoh, M., Yonemura, S., Nagafuchi, A., Tsukita, Sa., Tsukita, Sh., 1991, A 220-KD undercoat-constitutive protein: its specific localization at cadherin-based cell-cell adhesin sites. J. Cell Biol. 115: 1449–1462.PubMedCrossRefGoogle Scholar
  35. Kanai, H., Ochiai, A., Shibata, T., Oyama, S., Ushijima, S., Akimoto, S., Hiroashi, S., 1995, c-erb-B2 gene product directly associates with b-catenin and plakoglobin, Biochem. Biophys. Res. Commun. 208: 1067–1072.PubMedCrossRefGoogle Scholar
  36. Keon, B. A., Schafer, S., Kuhn, C., Grund, C., Franke, W. W., 1996, Symplekin, a novel type of tight junction plaque protein, J. Cell Biol. 134: 1003–1018.PubMedCrossRefGoogle Scholar
  37. Kim, S. K., 1995, Tight junctions, membrane-associated guanylate kinases and cell signalling. Curr. Opin. Cell. Biol. 7:641–649.PubMedCrossRefGoogle Scholar
  38. Kinch, M. S., Clark, G. J., Der, C. J., Burridge, K., 1995, Tyrosine phosphorylation regulates the adhesion of ras-transformed breast epithelia, J. Cell Biol. 130: 461–471.PubMedCrossRefGoogle Scholar
  39. Kypta, R. M., Su, H., and Reichardt, L. F., 1996, Association between a transmembrane protein tyrosine phosphatase and the cadherin-catenin complex, J. Cell Biol. 134: 1519–1529.PubMedCrossRefGoogle Scholar
  40. Lampugnani, M. G., Corada, M., Andriopoulou, P., Esser, S., Risau, W., and Dejana, E., Cell confluence regulates tyrosine phosphorylation of adherens junction components in endothelial cells, J. Cell Sci., in pressGoogle Scholar
  41. Li, C., and Poznansky, M. J., 1990, Characterization of the ZO-1 protein in endothelial and other cell lines, J. Cell Sci. 97: 231–237.PubMedGoogle Scholar
  42. Lue, R. A., Brandin, E., Chan, E. P., and Branton, D., 1996, Two independent domains of hDlg are sufficient for subcellular targeting: the PDZ1–2 conformational unit and an alternatively spliced domain, J. Cell Biol. 135: 1125–1137.PubMedCrossRefGoogle Scholar
  43. Matsumine, A., Ogai, A., Senda, T., Okumura, N., Satoh, K., Baeg, G. H., Kawahara, T., Kobayashi, S., Okada, M., Tohyoshima, K., and Akiyama, T., 1996, Binding of APC to the human homolog of the drosophila discs large tumor suppressor protein, Science 272: 1020–1023.PubMedCrossRefGoogle Scholar
  44. McCarthy, K. M., Skare, I. B., Stankewich, M. C., Furuse, M., Tsukita, S., Rogers, R. A., Lynch, R. D., and Schneeberger, E. E., 1996, Occludin is a functional component of the tight junction, J. Cell Sci. 109: 2287–2298.PubMedGoogle Scholar
  45. Miller, J. R., and Moon, R. T., 1996, Signal transduction through b-catenin and specification of cell fate during embryogenesis, Gen. Dev. 10: 2527–2539.CrossRefGoogle Scholar
  46. Molenaar, M., van de Wetering, M., Oosterwegel, M., Peterson-Maduro, J., Godsave, S., Korinek, V., Roose, J., Destree, O., and Clevers, H., 1996, XTcf-3 transcription factor mediates b-catenin-induced axis formation in Xenopus embryos, Cell 86: 391–399.PubMedCrossRefGoogle Scholar
  47. Newman, P. J., 1997, The biology of PECAM-1, J. Clin. Invest. 99: 3–8.PubMedCrossRefGoogle Scholar
  48. Nusse, R., 1997, A versatile transcriptional effector of wingless signalling, Cell 89: 321–323.PubMedCrossRefGoogle Scholar
  49. Orsulic, S., and Peifer, M., 1996, An in vivo structure-function study of Armadillo, the b-catenin homologue, reveals both separate and overlapping regions of the protein required for cell adhesion and for Wingless signaling, J. Cell Biol. 134: 1283–1300.PubMedCrossRefGoogle Scholar
  50. Peifer, M., 1995, Cell adhesion and signal transduction: the Armadillo connection, Trends Cell. Biol. 5: 224–229.PubMedCrossRefGoogle Scholar
  51. Rajasekaran, A.K., Hojo, M., Huima, T., and Rodriguez-Boulan, E., 1996, Catenins and zonula occludens-1 form a complex during early stages in the assembly of tight junctions, J. Cell Biol. 132:451–463.PubMedCrossRefGoogle Scholar
  52. Salomon, D., Ayalon, O., Patel-King, L., Hynes, R. O., and Geiger, B., 1992, Extrajunctional distribution of N-cadherin in cultured human endothelial cells, J. Cell Sci. 102: 1–11.Google Scholar
  53. Satoh, H., Zhoug, Y., Isomura, H., Saitoh, M., Enomoto, K., Sawada, M., and Mori, M., 1996, Localization of 7H6 tight junction-associated antigen along the cell border of vascular endothelial cells correlates with paracellular barrier function against ions, large molecules and cancer cells, Exp. Cell Res. 222: 269–274.PubMedCrossRefGoogle Scholar
  54. Schmelz, M., and Franke, W. W., 1993, Complexus adhaerens, a new group of desmoplakin-containing junctions in endothelial cells: the syndesmos connecting retothelial cells in lymph nodes, Eur. J. Cell Biol. 61: 274–289.PubMedGoogle Scholar
  55. Schnitzer, J. E., 1993, Update on the cellular and molecular basis of capillary permeability, Cardiovasc. Med. 3: 124–130.Google Scholar
  56. Simionescu, N., and Simionescu, M., 1991, Endothelial transport macromolecules: transcytosis and endocytosis, Cell Biol. Rev. 25: 5–80.PubMedGoogle Scholar
  57. Staddon, J. M., Herrenknecht, K., Smales, C., and Rubin, L. L., 1995, Evidence that tyrosine phosphorylation may increase tight junction permeability, J. Cell Sci. 108: 609–619.PubMedGoogle Scholar
  58. Staddon, J. M., and Rubin L. L., 1996, Cell adhesion, cell junctions and the blood brain barrier, Curr. Opin. Neurobiol. 6: 622–627.PubMedCrossRefGoogle Scholar
  59. Staddon, J. M., Saitou, M., Furuse, M., Tsukita, Sh., and Rubin, L. L., 1996, Occludin in endothelial cells, Mol. Biol. Cell. 7: 605aGoogle Scholar
  60. Stevenson, B. R., Siciliano, J. D., Mooseker, M. S., and Goodenough, D. A., 1986, Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia, J. Cell Biol. 103: 755–766.PubMedCrossRefGoogle Scholar
  61. Takeichi, M., 1993, Cadherins in cancer: implications for invasion and metastasis, Curr. Opin. Cell Biol. 5:806–811.PubMedCrossRefGoogle Scholar
  62. Tao, Y. S., Edwards, R. A., Tubb, B., Wang, S., Bryan, J., Mc Crea, P. D., 1996, b-catenin associates with the actin-bundling protein fascin in a noncadherin complex, J. Cell Biol. 134: 1271–1281.PubMedCrossRefGoogle Scholar
  63. Valiron, O., Chevrier, V., Usson, Y., Breviario, F., Job, D., and Dejana, E., 1996, Desmoplakin expression and organization at human umbilical vein endothelial cell-to-cell junctions. J. Cell Sci. 109: 2141–2149.PubMedGoogle Scholar
  64. Van Itallie, C. M., Balda, M. S., Anderson, J. M., 1995, Epidermal growth factor induces tyrosine phosphorylation and reorganization of the tight junction protein ZO-1 in A431 cells, J. Cell Sci. 108: 1735–1742.PubMedGoogle Scholar
  65. Vittet, D., Buchou, T., Schweitzer, A., Dejana, E., and Huber, P., Targeted null-mutation in the VE-cadherin gene impairs the organization of vascular- like structures in embryoid bodies, Proc. Natl. Acad. Sci. in press.Google Scholar
  66. Watabe, M., Nagafuchi, A., Tsukita, S., and Takeichi, M., 1994, Induction of polarized cell-cell association and retardation of growth by activation of the E-cadherin-catenin adhesion system in a dispersed carcinoma line, J. Cell Biol. 127: 247–256.PubMedCrossRefGoogle Scholar
  67. Wong V, Gumbiner BM: A synthetic peptide corresponding to the extracellular domain of occludin perturbs the tight junction permeability barrier. J Cell Biol 1997, 136: 399–409.PubMedCrossRefGoogle Scholar
  68. Woods DF, Hough C., Peel D, Callain G, Bryant PJ: Dlg protein is required for junction structure, cell polarity and proliferation control in Drosophila epithelia. J Cell Biol 1996, 134: 1469–1482.PubMedCrossRefGoogle Scholar
  69. Zhong Y, Saitoh T, Minase T, Sawada N, Enomoto K, Mori M: Monoclonal antibody 7H6 reacts with a novel tight junction-associated protein distinct from ZO-1, cingulin, and ZO-2. J Cell Biol 1993. 120: 477–483.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Pilar Navarro
    • 1
  • Maria Grazia Lampugnani
    • 1
  • Elisabetta Dejana
    • 1
  1. 1.Vascular Biology LaboratoryMario Negri Institute for Pharmacological ResearchMilanoItaly

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