Annals of Biomedical Engineering

, Volume 40, Issue 3, pp 568–577 | Cite as

Cell–Cell Junctional Proteins in Cardiovascular Mechanotransduction

Article

Abstract

Cell–cell junctional proteins play important structural and functional roles in several physiological systems. Recent studies have illuminated key aspects in the relationship of junctional proteins with normal cell and tissue function as well as various pathologies. In this review article, the roles of cell–cell junctional proteins will be presented in four classes: adherens junctions, desmosomes, gap junctions, and tight junctions, and discussed primarily in the context of cardiovascular cell and tissue physiology and pathophysiology. The functions of the proteins are described from the perspective of mechanotransductive regulation of physiological and disease processes, with focus being laid on more biomechanical aspects, such as cell adhesion, migration, and mechanosignaling.

Keywords

Adherens junction Desmosome Gap junction Tight junction Cardiovascular 

References

  1. 1.
    Abe, K., O. Chisaka, F. van Roy, and M. Takeichi. Stability of dendritic spines and synaptic contacts is controlled by alpha-N-catenin. Nat. Neurosci. 7:357–363, 2004.PubMedCrossRefGoogle Scholar
  2. 2.
    Albuquerque, M. L. C., and A. S. Flozak. Wound closure in sheared endothelial cells is enhanced by modulation of VE-cadherin expression and localization. Exp. Biol. Med. 227:1006–1016, 2002.Google Scholar
  3. 3.
    Asimaki, A., P. Syrris, T. Wichter, P. Matthias, J. E. Saffitz, and W. J. McKenna. A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Am. J. Hum. Genet. 81:964–973, 2007.PubMedCrossRefGoogle Scholar
  4. 4.
    Asimaki, A., H. Tandri, H. Huang, M. K. Halushka, S. Gautam, C. Basson, G. Thiene, A. Tsatsopoulou, N. Protonotarios, W. J. McKenna, H. Calkins, and J. E. Saffitz. A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. NEJM 360:1075–1084, 2009.PubMedCrossRefGoogle Scholar
  5. 5.
    Bamji, S. X. Cadherins: actin with the cytoskeleton to form synapses. Neuron 47:175–178, 2005.PubMedCrossRefGoogle Scholar
  6. 6.
    Bao, X., C. B. Clark, and J. A. Frangos. Temporal gradient in shear-induced signaling pathway: involvement of MAP kinase, c-fos, and connexin-43. Am. J. Physiol. Heart Circ. Physiol. 278:H1598–H1605, 2000.PubMedGoogle Scholar
  7. 7.
    Bazzoni, G., P. Tonetti, L. Manzi, M. R. Cera, G. Balconi, and E. Dejana. Expression of junctional adhesion molecule-A prevents spontaneous and random motility. J. Cell Sci. 118:623–632, 2005.PubMedCrossRefGoogle Scholar
  8. 8.
    Birchmeier, W., and J. Behrens. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim. Biophys. Acta 1198:11–26, 1993.Google Scholar
  9. 9.
    Chopra, A., E. Tabdanov, H. Patel, P. A. Janmey, and J. Y. Kresh. Cardiac myocyte remodeling mediated by N-cadherin-dependent mechanosensing. Am. J. Physiol. Heart Circ. Physiol. 300:H1252–H1256, 2011.PubMedCrossRefGoogle Scholar
  10. 10.
    De Maio, L., Y. S. Chang, T. W. Gardner, J. M. Tarbell, and D. A. Antonetti. Shear stress regulates occludin content and phosphorylation. Am. J. Physiol. Heart Circ. Physiol. 281:H105–H113, 2001.Google Scholar
  11. 11.
    De Paola, N., P. F. Davies, W. F. Pritchard, L. Florez, N. Harbeck, and D. C. Polacek. Spatial and temporal regulation of gap junction connexin43 in vascular endothelial cells exposed to controlled disturbed flows in vitro. Proc. Natl. Acad. Sci. USA 96:3154–3159, 1999.CrossRefGoogle Scholar
  12. 12.
    De Wever, O., W. Westbroek, A. Verloes, N. Bloemen, M. Bracke, C. Gespach, E. Bruyneel, and M. Mareel. Critical role of N-cadherin in myofibroblast invasion and migration in vitro stimulated by colon-cancer-cell-derived TGF-beta or wounding. J. Cell Sci. 117:4691–4703, 2004.PubMedCrossRefGoogle Scholar
  13. 13.
    Dekker, R. J., S. van Soest, R. D. Fontijn, S. Salamanca, P. G. de Groot, E. VanBavel, H. Pannekoek, and A. J. Horrevoets. Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Kruppel-like factor (KLF-2). Blood 100:1689–1698, 2002.PubMedCrossRefGoogle Scholar
  14. 14.
    Doyle, D. D., G. E. Goings, J. Upshaw-Earley, E. Page, B. Ranscht, and H. C. Palfrey. T-cadherin is a major glycophosphoinositol-anchored protein associated with noncaveolar detergent-insoluble domains of the cardiac sarcolemma. J. Biol. Chem. 273:6937–6943, 1998.PubMedCrossRefGoogle Scholar
  15. 15.
    Dusek, R. L., L. M. Godsel, and K. J. Green. Discriminating roles of desmosomal cadherins: beyond desmosomal adhesion. J. Dermatol. Sci. 45:7–21, 2007.PubMedCrossRefGoogle Scholar
  16. 16.
    Evans, W. H., and P. E. Martin. Gap junctions: structure and function. Mol. Membr. Biol. 19:121–136, 2002.PubMedCrossRefGoogle Scholar
  17. 17.
    Gehmlich, K., P. D. Lambiase, A. Asimaki, E. J. Ciaccio, E. Ehler, P. Syrris, J. E. Saffitz, and W. J. McKenna. A novel desmocollin-2 mutation reveals insights into the molecular link between desmosomes and gap junctions. Heart Rhythm 8:711–718, 2011.PubMedCrossRefGoogle Scholar
  18. 18.
    Gopalan, S. M., C. Flaim, S. N. Bhatia, M. Hoshijima, R. Knoell, K. R. Chien, J. H. Omens, and A. McCulloch. Anisotrophic stretch-induced hypertrophy in neonatal ventricular myocytes micropatterned on deformable elastomers. Biotechnol. Bioeng. 81:578–587, 2002.CrossRefGoogle Scholar
  19. 19.
    Grossmann, K. S., C. Grund, J. Huelsken, M. Behrend, B. Erdmann, W. W. Franke, and W. Birchmeier. Requirement of plakophilin 2 for heart morphogenesis and cardiac junction formation. J. Cell Biol. 167:149–160, 2004.PubMedCrossRefGoogle Scholar
  20. 20.
    Gutstein, E., F. Liu, M. B. Meyers, A. Choo, and G. I. Fishman. The organization of adherens junctions and desmosomes at the cardiac intercalated disk is independent of gap junctions. J. Cell Sci. 116:875–885, 2003.PubMedCrossRefGoogle Scholar
  21. 21.
    Hinz, B., P. Pittet, J. Smith-Clerc, C. Chaponnier, and J. J. Meister. Myofibroblast development is characterized by specific cell–cell adherens junctions. Mol. Biol. Cell 15:4310–4320, 2004.PubMedCrossRefGoogle Scholar
  22. 22.
    Huang, H., A. Asimaki, D. Lo, W. McKenna, and J. E. Saffitz. Disparate effects of different mutation in plakoglobin on cell mechanical behavior. Cell Motil. Cytoskelet. 65:964–978, 2008.CrossRefGoogle Scholar
  23. 23.
    Huang, H., F. Cruz, and G. Bazzoni. Junctional adhesion molecule-A regulates cell migration and resistance to shear stress. J. Cell. Physiol. 209:122–130, 2006.PubMedCrossRefGoogle Scholar
  24. 24.
    Huber, O. Structure and function of desmosomal proteins and their role in development and disease. Cell. Mol. Life Sci. 60:1872–1890, 2003.PubMedCrossRefGoogle Scholar
  25. 25.
    Imamura, Y., M. Itoh, Y. Maeno, S. Tsukita, and A. Nagafuchi. Functional domains of catenin required for the strong state of cadherin cell adhesion. J. Cell Biol. 144:1311–1322, 1999.PubMedCrossRefGoogle Scholar
  26. 26.
    Ivanov, D., M. Philippova, R. Allenspach, P. Erne, and T. Resink. Cell adhesion molecule T-cadherin regulates vascular cell adhesion, phenotype and motility. Exp. Cell Res. 293:207–214, 2004.PubMedCrossRefGoogle Scholar
  27. 27.
    Kartenbeck, J., W. W. Franke, J. G. Moser, and U. Stoffels. Specific attachment of desmin filaments to desmosomal plaques in cardiac myocytes. EMBO J. 2:735–742, 1983.PubMedGoogle Scholar
  28. 28.
    Kostetskii, I., J. Li, Y. Xiong, R. Zhou, V. A. Ferrari, V. V. Patel, J. D. Molkentin, and G. L. Radice. Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disk structure. Circ. Res. 96:346–354, 2005.PubMedCrossRefGoogle Scholar
  29. 29.
    Kostin, S., S. Dammer, S. Hein, W. P. Kloverkorn, E. P. Bauer, and J. Schaper. Connexin 43 expression and distribution in compensated and decompensated cardiac hypertrophy in patients with aortic stenosis. Cardiovasc. Res. 62:426–436, 2004.PubMedCrossRefGoogle Scholar
  30. 30.
    Kostin, S., S. Hein, E. P. Bauer, and J. Schaper. Spatiotemporal development and distribution of intercellular junctions in adult rat cardiomyocytes in culture. Circ. Res. 85:154–167, 1999.PubMedGoogle Scholar
  31. 31.
    Kumar, N. M., and N. B. Gilula. The gap junction communication channel. Cell 84:381–388, 1996.PubMedCrossRefGoogle Scholar
  32. 32.
    Lampugnani, M. G., A. Zanetti, F. Breviario, G. Balconi, F. Orsenigo, M. Corada, R. Spagnuolo, M. Betson, V. Braga, and E. Dejana. VE-cadherin regulates endothelial actin activating Rac and increasing membrane association of Tiam. Mol. Biol. Cell 13:1175–1189, 2002.PubMedCrossRefGoogle Scholar
  33. 33.
    Li, S., N. F. Huang, and S. Hsu. Mechanotransduction in endothelial cell migration. J. Cell. Biochem. 96:1110–1126, 2005.PubMedCrossRefGoogle Scholar
  34. 34.
    Li, J., M. D. Levin, Y. Xiong, N. Petrenko, V. V. Patel, and G. L. Radice. N-cadherin haploinsufficiency affects cardiac gap junctions and arrhythmic susceptibility. J. Mol. Cell. Cardiol. 44:597–606, 2008.PubMedCrossRefGoogle Scholar
  35. 35.
    Li, M. W., D. D. Mruk, W. M. Lee, and C. Y. Cheng. Connexin 43 and plakophilin-2 as a protein complex that regulates blood–testis barrier dynamics. Proc. Natl. Acad. Sci. USA 106:10213–10218, 2009.PubMedCrossRefGoogle Scholar
  36. 36.
    Li, J., V. V. Patel, I. Kostetshii, Y. Xiong, A. F. Chu, J. T. Jacobson, C. Yu, G. E. Morely, J. D. Molkentin, and G. L. Radice. Cardiac-specific loss of N-cadherin leads to alteration in connexins with conduction slowing and arrhythmogenesis. Circ. Res. 97:474–481, 2005.PubMedCrossRefGoogle Scholar
  37. 37.
    Lisewski, U., Y. Shi, U. Wrackmeyer, R. Fischer, C. Chen, A. Schirdewan, R. Juttner, F. Rathjen, W. Poller, M. H. Radke, and M. Gotthardt. The tight junction protein CAR regulates cardiac conduction and cell–cell communication. J. Exp. Med. 205:2369–2379, 2008.PubMedCrossRefGoogle Scholar
  38. 38.
    Marsden, M., and D. W. Simone. Integrin–ECM interactions regulate cadherin-dependent cell adhesion and are required for convergent extension in Xenopus. Curr. Biol. 13:1182–1191, 2003.PubMedCrossRefGoogle Scholar
  39. 39.
    Martin-Padura, I., S. Lostaglio, M. Schneemann, L. Williams, M. Romano, P. Fruscella, C. Panzeri, A. Stoppacciaro, L. Ruco, A. Villa, D. Simmons, and E. Dejana. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J. Cell Biol. 142:117–127, 1998.PubMedCrossRefGoogle Scholar
  40. 40.
    Maruthamuthu, V., B. Sabass, U. S. Schwarz, and M. L. Gardel. Cell–ECM traction force modulates endogenous tension at cell–cell contacts. Proc. Natl. Acad. Sci. USA 12:4708–4713, 2011.CrossRefGoogle Scholar
  41. 41.
    McKoy, G., N. Protonotarios, A. Crosby, A. Tsatsopoulou, A. Anastasakis, and A. Coonar. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 355:2119–2212, 2000.PubMedCrossRefGoogle Scholar
  42. 42.
    Mitic, L. L., and J. M. Anderson. Molecular architecture of tight junctions. Annu. Rev. Physiol. 69:121–141, 1998.CrossRefGoogle Scholar
  43. 43.
    Mitic, L. L., C. M. Van Itallie, and J. M. Anderson. Molecular physiology and pathophysiology of tight junctions I. Tight junction structure and function: lessons from mutant animals and proteins. Am. J. Physiol. Gastrointest. Liver Physiol. 279:G250–G254, 2000.PubMedGoogle Scholar
  44. 44.
    Nagafuchi, A. Molecular architecture of adherens junctions. Curr. Opin. Cell Biol. 13:600–603, 2001.PubMedCrossRefGoogle Scholar
  45. 45.
    Nelson, C. M., D. M. Pirone, J. L. Tan, and C. S. Chen. Vascular endothelial-cadherin regulates cytoskeletal tension, cell spreading, and focal adhesions by stimulating RhoA. Mol. Biol. Cell 15:2943–2953, 2004.PubMedCrossRefGoogle Scholar
  46. 46.
    Norman, M., M. Simpson, J. Mogensen, A. Shaw, S. Hughes, P. Syrris, S. Sen-Chowdhry, E. Rowland, A. Crosby, and W. J. McKenna. Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy. Circulation 112:636–642, 2005.PubMedCrossRefGoogle Scholar
  47. 47.
    Olk, S., G. Zoidl, and R. Dermietzel. Connexins, cell motility, and the cytoskeleton. Cell Motil. Cytoskelet. 66:1000–1016, 2009.CrossRefGoogle Scholar
  48. 48.
    Perryn, E. D., A. Czirok, and C. D. Little. Vascular sprout formation entails tissue deformations and VE-cadherin-dependent cell-autonomous motility. Dev. Biol. 313(2):545–555, 2008.PubMedCrossRefGoogle Scholar
  49. 49.
    Provost, E., and D. L. Rimm. Controversies at the cytoplasmic face of the cadherin-based adhesion complex. Curr. Opin. Cell Biol. 11:567–572, 1999.PubMedCrossRefGoogle Scholar
  50. 50.
    Radice, G. L., H. Rayburn, H. Matsunami, K. A. Knudsen, M. Takeichi, and R. O. Hynes. Developmental defects in mouse embryos lacking N-cadherins. Dev. Biol. 181:64–78, 1997.PubMedCrossRefGoogle Scholar
  51. 51.
    Raghavan, S., and E. Fuchs. Getting under the skin of epidermal morphogenesis. Nat. Rev. Genet. 3:199–209, 2002.PubMedCrossRefGoogle Scholar
  52. 52.
    Resink, T. J., M. Philippova, M. B. Joshi, E. Kyriakakis, and P. Erne. Cadherins in cardiovascular disease. Swiss Med. Wkly. 139:122–134, 2009.PubMedGoogle Scholar
  53. 53.
    Rhee, D. Y., X. Q. Zhao, R. J. B. Francis, G. Y. Huang, J. D. Mably, and C. W. Lo. Connexin 43 regulates epicardial cell polarity and migration in coronary vascular development. Development 136:3185–3193, 2009.PubMedCrossRefGoogle Scholar
  54. 54.
    Ruhrberg, C., and F. M. Watt. The plakin family: versatile organizers of cytoskeletal architecture. Curr. Opin. Genet. Dev. 7:392–397, 1997.PubMedCrossRefGoogle Scholar
  55. 55.
    Runswick, S. K., M. J. O’Hare, L. Jones, C. H. Steull, and D. R. Garrod. Desmosomal adhesion regulates epithelial morphogenesis and cell positioning. Nat. Cell Biol. 3:823–830, 2001.PubMedCrossRefGoogle Scholar
  56. 56.
    Saffitz, J. E. Dependence of electrical coupling on mechanical coupling in cardiac myocytes: insights gained from cardiomyopathies caused by defects in cell–cell connections. Ann. N. Y. Acad. Sci. 1047:336–344, 2005.PubMedCrossRefGoogle Scholar
  57. 57.
    Sanford, J. L., J. D. Edwards, T. A. Mays, B. Gong, A. P. Merriam, and J. A. Rafael-Fortney. Claudin-5 localizes to the lateral membranes of cardiomyoctyes and is altered in utrophin/dystrophin-deficient cariomyopathic mice. J. Mol. Cell. Cardiol. 38:323–332, 2005.PubMedCrossRefGoogle Scholar
  58. 58.
    Schmidt, A., H. W. Heid, S. Schafer, U. A. Nuber, R. Zimbelmann, and W. W. Franke. Desmosomes and cytoskeletal architecture in epithelial differentiation: cell type-specific plaque components and intermediate filament anchorage. Eur. J. Cell Biol. 65:229–245, 1994.PubMedGoogle Scholar
  59. 59.
    Sen-Chowdhry, S., P. Syrris, and W. J. McKenna. Desmoplakin disease in arrhythmogenic right ventricular cardiomyopathy: early genotype–phenotype studies. Eur. Heart J. 26:1582–1584, 2005.PubMedCrossRefGoogle Scholar
  60. 60.
    Severson, E. A., W. Y. Lee, C. T. Capaldo, A. Nusrat, and C. A. Parkos. Junctional adhesion molecule A interacts with Afadin and PDZ-GEF2 to activate Rap1A, regulate beta1 integrin levels, and enhance cell migration. Mol. Biol. Cell 20:1916–1925, 2009.PubMedCrossRefGoogle Scholar
  61. 61.
    Sheikh, F., Y. Chen, X. Liang, A. Hirschy, A. E. Stenbit, Y. Gu, N. D. Dalton, T. Yajima, Y. Lu, K. Y. Knowlton, K. L. Peterson, J. Perriard, and J. Chen. Alpha-E-catenin inactivation disrupts the cardiomyocyte adherens junction, resulting in cardiomyopathy and susceptibility to wall rupture. Circulation 114:1046–1055, 2006.PubMedCrossRefGoogle Scholar
  62. 62.
    Simcha, I., B. Geinger, S. Yehuda-Levenberg, D. Salomon, and A. Ben-Ze’ev. Suppression of tumorigenicity by plakoglobin: an augmenting effect of N-cadherin. J. Cell Biol. 133:199–209, 1996.PubMedCrossRefGoogle Scholar
  63. 63.
    Syrris, P., D. Ward, A. Asimaki, S. Sen-Chowdhry, H. Y. Ebrahim, A. Evans, N. Hitomi, N. M. Norman, A. Pantazis, A. L. Shaw, P. M. Elliott, and W. J. McKenna. Clinical expression of plakophilin-2 mutation in familial arrhythmogenic right ventricular cardiomyopathy. Circulation 113:356–364, 2006.PubMedCrossRefGoogle Scholar
  64. 64.
    Takeichi, M. Morphogenetic roles of classic cadherins. Curr. Opin. Cell Biol. 7:619–627, 1995.PubMedCrossRefGoogle Scholar
  65. 65.
    Tarbell, J. M. Shear stress and the endothelial transport barrier. Cardiovasc. Res. 87:320–330, 2010.PubMedCrossRefGoogle Scholar
  66. 66.
    Thomas, S. A., R. B. Schuessler, C. I. Berul, M. A. Beardslee, E. C. Beyer, M. E. Mendelsohn, and J. E. Saffitz. Disparate effects of deficient expression of connexin43 on atrial and ventricular conduction: evidence for chamber-specific molecular determinants of conduction. Circulation 97:686–691, 1998.PubMedGoogle Scholar
  67. 67.
    Tomasek, J. J., G. Gabbiani, B. Hinz, C. Chaponnier, and R. A. Brown. Myofibroblasts and mechano-regulation of connective tissue remodeling. Nat. Rev. Mol. Cell Biol. 3:349–363, 2002.PubMedCrossRefGoogle Scholar
  68. 68.
    Uchida, N., Y. Honjo, K. R. Johnson, M. J. Wheelock, and M. Takeichi. The catenin/cadherin adhesion system is localized in synaptic junctions bordering transmitter release zones. J. Cell Biol. 135:767–779, 1996.PubMedCrossRefGoogle Scholar
  69. 69.
    Van Itallie, C. M., and J. M. Anderson. Claudins and epithelial paracellular transport. Annu. Rev. Physiol. 68:403–429, 2006.PubMedCrossRefGoogle Scholar
  70. 70.
    Vermeer, P. D., L. A. Einwalter, T. O. Moninger, T. Rokhlina, J. A. Kern, J. Zabner, and M. J. Welsh. Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature 422:322–326, 2003.PubMedCrossRefGoogle Scholar
  71. 71.
    Volk, T., and B. Geiger. A-CAM: a 135-kD receptor of intercellular adherens junctions. I. Immunoelectron microscopic localization and biochemical studies. J. Cell Biol. 103:1441–1450, 1986.PubMedCrossRefGoogle Scholar
  72. 72.
    Wang, T. L., Y. Z. Tseng, and H. Chang. Regulation of connexin 43 gene expression by cyclical mechanical stretch in neonatal rat cardiomyocytes. Biochem. Biophys. Res. Commun. 267:551–557, 2000.PubMedCrossRefGoogle Scholar
  73. 73.
    Wei, C. J., R. Francis, X. Xu, and C. W. Lo. Connexin43 associated with an N-cadherin-containing multiprotein complex is required for gap junction formation in NIH3T3 cells. J. Biol. Chem. 280:19925–19936, 2005.PubMedCrossRefGoogle Scholar
  74. 74.
    Yamada, K., K. G. Green, A. M. Samarel, and J. E. Saffitz. Distinct pathways regulate expression of cardiac electrical and mechanical junction proteins in response to stretch. Circ. Res. 97:346–353, 2005.PubMedCrossRefGoogle Scholar
  75. 75.
    Yamada, N., T. Okano, H. Sakai, F. Karikusa, Y. Sawasaki, and Y. Sakurai. Thermo responsive polymeric surfaces; control of attachment and detachment of cultured cells. Makromol. Chem. Rapid Commun. 11:571–576, 1990.CrossRefGoogle Scholar
  76. 76.
    Yap, A. S., W. M. Brieher, and B. M. Gumbiner. Molecular and functional analysis of cadherin-based adherens junctions. Annu. Rev. Cell. Dev. Biol. 13:119–146, 1997.PubMedCrossRefGoogle Scholar
  77. 77.
    Zhuang, J., K. A. Yamada, J. E. Saffitz, and A. G. Kleber. Pulsatile stretch remodels cell-to-cell communication in cultured myocytes. Circ. Res. 87:316–322, 2000.PubMedGoogle Scholar

Copyright information

© Biomedical Engineering Society 2011

Authors and Affiliations

  1. 1.Biomedical Engineering Departmental OfficeColumbia UniversityNew YorkUSA

Personalised recommendations