Advertisement

Cell and Tissue Research

, Volume 355, Issue 3, pp 545–555 | Cite as

Mechanical control of the endothelial barrier

  • Joppe Oldenburg
  • Johan de RooijEmail author
Review

Abstract

The integrity of the endothelial barrier is controlled by the combined action of chemical and mechanical signaling systems. Permeability-regulating factors signal through small GTPases to regulate the architecture of the cytoskeleton and this has a strong impact on the morphology and stability of VE-cadherin-based cell–cell junctions. The details of how structural and mechanical properties of the actin cytoskeleton influence cell–cell adhesion and how this impacts the dynamic regulation of the endothelial barrier, are beginning to be elucidated. In this review, we discuss the physical and regulatory interactions between the VE-cadherin complex and the actomysoin cytoskeleton, as they are the main determinants of cell–cell adhesion and the mechanical architecture of the cytoskeleton. We discuss, based on recent in vitro data, how a balance between Linear Adherens Junctions, paralleled by cortical actin bundles and Focal Adherens Junctions, connected to radial action bundles, determines endothelial barrier function. We discuss how small GTPases control this balance by regulating the spatial organization and mechanics of actomyosin. We propose a hypothetical model of how biochemical and mechanical signals cooperate locally, at the actomyosin–adhesion interface to open and re-seal the barrier in a rapid and controlled manner.

Keywords

VE–cadherin Actomyosin Cell–cell adhesion Mechanotransduction Endothelial barrier 

References

  1. Ando K, Fukuhara S et al (2013) Rap1 potentiates endothelial cell junctions by spatially controlling myosin II activity and actin organization. J Cell Biol 202(6):901–916PubMedCentralPubMedCrossRefGoogle Scholar
  2. Anthis NJ, Campbell ID (2011) The tail of integrin activation. Trends Biochem Sci 36(4):191–198PubMedCentralPubMedCrossRefGoogle Scholar
  3. Asakura T, Nakanishi H et al (1999) Similar and differential behaviour between the nectin-afadin-ponsin and cadherin-catenin systems during the formation and disruption of the polarized junctional alignment in epithelial cells. Genes Cells 4(10):573–581PubMedCrossRefGoogle Scholar
  4. Bartolini F, Moseley JB et al (2008) The formin mDia2 stabilizes microtubules independently of its actin nucleation activity. J Cell Biol 181(3):523–536PubMedCentralPubMedCrossRefGoogle Scholar
  5. Baumer Y, Drenckhahn D et al (2008) cAMP induced Rac 1-mediated cytoskeletal reorganization in microvascular endothelium. Histochem Cell Biol 129(6):765–778PubMedCrossRefGoogle Scholar
  6. Bazzoni G (2006) Endothelial tight junctions: permeable barriers of the vessel wall. Thromb Haemost 95(1):36–42PubMedGoogle Scholar
  7. Birukov KG (2009) Small GTPases in mechanosensitive regulation of endothelial barrier. Microvasc Res 77(1):46–52PubMedCentralPubMedCrossRefGoogle Scholar
  8. Birukova AA, Arce FT et al (2009) Endothelial permeability is controlled by spatially defined cytoskeletal mechanics: atomic force microscopy force mapping of pulmonary endothelial monolayer. Nanomedicine 5(1):30–41PubMedCentralPubMedCrossRefGoogle Scholar
  9. Birukova AA, Fu P et al (2012) Afadin controls p120-catenin-ZO-1 interactions leading to endothelial barrier enhancement by oxidized phospholipids. J Cell Physiol 227(5):1883–1890PubMedCentralPubMedCrossRefGoogle Scholar
  10. Birukova AA, Tian X et al (2013) Rap-afadin axis in control of Rho signaling and endothelial barrier recovery. Mol Biol Cell 24(17):2678–2688PubMedCentralPubMedCrossRefGoogle Scholar
  11. Bogatcheva NV, Verin AD (2008) The role of cytoskeleton in the regulation of vascular endothelial barrier function. Microvasc Res 76(3):202–207PubMedCentralPubMedCrossRefGoogle Scholar
  12. Brieher WM, Yap AS (2013) Cadherin junctions and their cytoskeleton(s). Curr Opin Cell Biol 25(1):39–46PubMedCrossRefGoogle Scholar
  13. Calderwood DA, Campbell ID et al (2013) Talins and kindlins: partners in integrin-mediated adhesion. Nat Rev Mol Cell Biol 14(8):503–517PubMedCrossRefGoogle Scholar
  14. Carisey A, Tsang R et al (2013) Vinculin regulates the recruitment and release of core focal adhesion proteins in a force-dependent manner. Curr Biol 23(4):271–281PubMedCentralPubMedCrossRefGoogle Scholar
  15. Chen XL, Nam JO et al (2012) VEGF-induced vascular permeability is mediated by FAK. Dev Cell 22(1):146–157PubMedCentralPubMedCrossRefGoogle Scholar
  16. Choi HJ, Pokutta S et al (2012) alphaE-catenin is an autoinhibited molecule that coactivates vinculin. Proc Natl Acad Sci USA 109(22):8576–8581PubMedCentralPubMedCrossRefGoogle Scholar
  17. Cohen LA, Guan JL (2005) Mechanisms of focal adhesion kinase regulation. Curr Cancer Drug Targets 5(8):629–643PubMedCrossRefGoogle Scholar
  18. Conway DE, Breckenridge MT et al (2013) Fluid shear stress on endothelial cells modulates mechanical tension across VE-cadherin and PECAM-1. Curr Biol 23(11):1024–1030PubMedCrossRefGoogle Scholar
  19. Dejana E, Orsenigo F et al (2008) The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 121(Pt 13):2115–2122PubMedCrossRefGoogle Scholar
  20. Del Zoppo GJ, Milner R et al (2006) Vascular matrix adhesion and the blood–brain barrier. Biochem Soc Trans 34(Pt 6):1261–1266PubMedGoogle Scholar
  21. DePianto D, Coulombe PA (2004) Intermediate filaments and tissue repair. Exp Cell Res 301(1):68–76PubMedCrossRefGoogle Scholar
  22. Gavard J (2009) “Breaking the VE-cadherin bonds“. FEBS Lett 583(1):1–6PubMedCrossRefGoogle Scholar
  23. Gavard J, Gutkind JS (2006) ‷VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 8(11):1223–1234PubMedCrossRefGoogle Scholar
  24. Geneste O, Copeland JW et al (2002) LIM kinase and Diaphanous cooperate to regulate serum response factor and actin dynamics. J Cell Biol 157(5):831–838PubMedCentralPubMedCrossRefGoogle Scholar
  25. Glading A, Han J et al (2007) KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions. J Cell Biol 179(2):247–254PubMedCentralPubMedCrossRefGoogle Scholar
  26. Hahn C, Schwartz MA (2009) Mechanotransduction in vascular physiology and atherogenesis. Nat Rev Mol Cell Biol 10(1):53–62PubMedCentralPubMedCrossRefGoogle Scholar
  27. Haselton FR, Heimark RL (1997) Role of cadherins 5 and 13 in the aortic endothelial barrier. J Cell Physiol 171(3):243–251PubMedCrossRefGoogle Scholar
  28. Hoelzle MK, Svitkina T (2012) The cytoskeletal mechanisms of cell-cell junction formation in endothelial cells. Mol Biol Cell 23(2):310–323PubMedCentralPubMedCrossRefGoogle Scholar
  29. Homan SM, Mercurio AM et al (1998) Endothelial cells assemble two distinct alpha6beta4-containing vimentin-associated structures: roles for ligand binding and the beta4 cytoplasmic tail. J Cell Sci 111(Pt 18):2717–2728PubMedGoogle Scholar
  30. Hoshino T, Sakisaka T et al (2005) Regulation of E-cadherin endocytosis by nectin through afadin, Rap1, and p120ctn. J Biol Chem 280(25):24095–24103PubMedCrossRefGoogle Scholar
  31. Huang C, Rajfur Z et al (2009) Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration. Nat Cell Biol 11(5):624–630PubMedCentralPubMedCrossRefGoogle Scholar
  32. Huveneers S, Oldenburg J et al (2012) Vinculin associates with endothelial VE-cadherin junctions to control force-dependent remodeling. J Cell Biol 196(5):641–652PubMedCentralPubMedCrossRefGoogle Scholar
  33. Ingber DE (2002) Mechanical signaling and the cellular response to extracellular matrix in angiogenesis and cardiovascular physiology. Circ Res 91(10):877–887PubMedCrossRefGoogle Scholar
  34. Jansen S, Collins A et al (2011) Mechanism of actin filament bundling by fascin. J Biol Chem 286(34):30087–30096PubMedCentralPubMedCrossRefGoogle Scholar
  35. Komarova YA, Huang F et al (2012) VE-cadherin signaling induces EB3 phosphorylation to suppress microtubule growth and assemble adherens junctions. Mol Cell 48(6):914–925PubMedCentralPubMedCrossRefGoogle Scholar
  36. Konstantoulaki M, Kouklis P et al (2003) Protein kinase C modifications of VE-cadherin, p120, and beta-catenin contribute to endothelial barrier dysregulation induced by thrombin. Am J Physiol Lung Cell Mol Physiol 285(2):L434–L442PubMedGoogle Scholar
  37. Krishnan R, Klumpers DD et al (2011) Substrate stiffening promotes endothelial monolayer disruption through enhanced physical forces. Am J Physiol Cell Physiol 300(1):C146–C154PubMedCentralPubMedCrossRefGoogle Scholar
  38. Lafuente EM, van Puijenbroek AA et al (2004) RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesion. Dev Cell 7(4):585–595PubMedCrossRefGoogle Scholar
  39. Lampugnani MG, Corada M et al (1995) The molecular organization of endothelial cell to cell junctions: differential association of plakoglobin, beta-catenin, and alpha-catenin with vascular endothelial cadherin (VE-cadherin). J Cell Biol 129(1):203–217PubMedCrossRefGoogle Scholar
  40. Le Boeuf F, Houle F et al (2006) Phosphorylation of focal adhesion kinase (FAK) on Ser732 is induced by rho-dependent kinase and is essential for proline-rich tyrosine kinase-2-mediated phosphorylation of FAK on Tyr407 in response to vascular endothelial growth factor. Mol Biol Cell 17(8):3508–3520PubMedCentralPubMedCrossRefGoogle Scholar
  41. le Duc Q, Shi Q et al (2010) Vinculin potentiates E-cadherin mechanosensing and is recruited to actin-anchored sites within adherens junctions in a myosin II-dependent manner. J Cell Biol 189(7):1107–1115PubMedCentralPubMedCrossRefGoogle Scholar
  42. Lee HS, Anekal P et al (2013) Two modes of integrin activation form a binary molecular switch in adhesion maturation. Mol Biol Cell 24(9):1354–1362PubMedCentralPubMedCrossRefGoogle Scholar
  43. Liu Z, Tan JL et al (2010) Mechanical tugging force regulates the size of cell-cell junctions. Proc Natl Acad Sci USA 107(22):9944–9949PubMedCentralPubMedCrossRefGoogle Scholar
  44. Lum H, Malik AB (1996) Mechanisms of increased endothelial permeability. Can J Physiol Pharmacol 74(7):787–800PubMedGoogle Scholar
  45. Mierke CT (2011) Cancer cells regulate biomechanical properties of human microvascular endothelial cells. J Biol Chem 286(46):40025–40037PubMedCentralPubMedCrossRefGoogle Scholar
  46. Mochizuki N (2009) Vascular integrity mediated by vascular endothelial cadherin and regulated by sphingosine 1-phosphate and angiopoietin-1. Circ J 73(12):2183–2191PubMedCrossRefGoogle Scholar
  47. Navarro P, Caveda L et al (1995) Catenin-dependent and -independent functions of vascular endothelial cadherin. J Biol Chem 270(52):30965–30972PubMedCrossRefGoogle Scholar
  48. Nemethova M, Auinger S et al (2008) Building the actin cytoskeleton: filopodia contribute to the construction of contractile bundles in the lamella. J Cell Biol 180(6):1233–1244PubMedCentralPubMedCrossRefGoogle Scholar
  49. Pannekoek WJ, Linnemann JR et al (2013) Rap1 and Rap2 antagonistically control endothelial barrier resistance. PLoS ONE 8(2):e57903PubMedCentralPubMedCrossRefGoogle Scholar
  50. Pannekoek WJ, van Dijk JJ et al (2011) Epac1 and PDZ-GEF cooperate in Rap1 mediated endothelial junction control. Cell Signal 23(12):2056–2064PubMedCrossRefGoogle Scholar
  51. Pokutta S, Drees F et al (2002) Biochemical and structural definition of the l-afadin- and actin-binding sites of alpha-catenin. J Biol Chem 277(21):18868–18874PubMedCentralPubMedCrossRefGoogle Scholar
  52. Pollard TD, Cooper JA (2009) Actin, a central player in cell shape and movement. Science 326(5957):1208–1212PubMedCentralPubMedCrossRefGoogle Scholar
  53. Post A, Pannekoek WJ et al (2013) Rasip1 mediates Rap1 regulation of Rho in endothelial barrier function through ArhGAP29. Proc Natl Acad Sci USA 110(28):11427–11432PubMedCentralPubMedCrossRefGoogle Scholar
  54. Rangarajan ES, Izard T (2012) The cytoskeletal protein alpha-catenin unfurls upon binding to vinculin. J Biol Chem 287(22):18492–18499PubMedCentralPubMedCrossRefGoogle Scholar
  55. Rangarajan ES, Izard T (2013) Dimer asymmetry defines alpha-catenin interactions. Nat Struct Mol Biol 20(2):188–193PubMedCentralPubMedCrossRefGoogle Scholar
  56. Rehm K, Panzer L et al (2013) Drebrin preserves endothelial integrity by stabilizing nectin at adherens junctions. J Cell Sci 126(Pt 16):3756–3769PubMedCrossRefGoogle Scholar
  57. Roman BL, Pekkan K (2012) Mechanotransduction in embryonic vascular development. Biomech Model Mechanobiol 11(8):1149–1168PubMedCrossRefGoogle Scholar
  58. Sahai E, Marshall CJ (2002) ROCK and Dia have opposing effects on adherens junctions downstream of Rho. Nat Cell Biol 4(6):408–415PubMedCrossRefGoogle Scholar
  59. Schmidt TT, Tauseef M et al (2013) Conditional deletion of FAK in mice endothelium disrupts lung vascular barrier function due to destabilization of RhoA and Rac1 activities. Am J Physiol Lung Cell Mol Physiol 305(4):L291–L300PubMedCrossRefGoogle Scholar
  60. Schulte D, Kuppers V et al (2011) Stabilizing the VE-cadherin-catenin complex blocks leukocyte extravasation and vascular permeability. EMBO J 30(20):4157–4170PubMedCentralPubMedCrossRefGoogle Scholar
  61. Schwartz EL (2009) Antivascular actions of microtubule-binding drugs. Clin Cancer Res 15(8):2594–2601PubMedCentralPubMedCrossRefGoogle Scholar
  62. Shewan AM, Maddugoda M et al (2005) Myosin 2 is a key Rho kinase target necessary for the local concentration of E-cadherin at cell-cell contacts. Mol Biol Cell 16(10):4531–4542PubMedCentralPubMedCrossRefGoogle Scholar
  63. Somlyo AP, Somlyo AV (2003) Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol Rev 83(4):1325–1358PubMedGoogle Scholar
  64. Spindler V, Schlegel N et al (2010) Role of GTPases in control of microvascular permeability. Cardiovasc Res 87(2):243–253PubMedCrossRefGoogle Scholar
  65. Stengel K, Zheng Y (2011) Cdc42 in oncogenic transformation, invasion, and tumorigenesis. Cell Signal 23(9):1415–1423PubMedCentralPubMedCrossRefGoogle Scholar
  66. Stockton RA, Schaefer E et al (2004) p21-activated kinase regulates endothelial permeability through modulation of contractility. J Biol Chem 279(45):46621–46630PubMedCrossRefGoogle Scholar
  67. Stockton RA, Shenkar R et al (2010) Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity. J Exp Med 207(4):881–896PubMedCentralPubMedCrossRefGoogle Scholar
  68. Svitkina T (2007) Electron microscopic analysis of the leading edge in migrating cells. Methods Cell Biol 79:295–319PubMedCrossRefGoogle Scholar
  69. Taddei A, Giampietro C et al (2008) Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5. Nat Cell Biol 10(8):923–934PubMedCrossRefGoogle Scholar
  70. Tawa H, Rikitake Y et al (2010) Role of afadin in vascular endothelial growth factor- and sphingosine 1-phosphate-induced angiogenesis. Circ Res 106(11):1731–1742PubMedCrossRefGoogle Scholar
  71. Timmerman I, Hoogenboezem M et al (2012) The tyrosine phosphatase SHP2 regulates recovery of endothelial adherens junctions through control of beta-catenin phosphorylation. Mol Biol Cell 23(21):4212–4225PubMedCentralPubMedCrossRefGoogle Scholar
  72. Twiss F, de Rooij J (2013) Cadherin mechanotransduction in tissue remodeling. Cell Mol Life Sci 70(21):4101–4116PubMedCrossRefGoogle Scholar
  73. Twiss F, Le Duc Q et al (2012) Vinculin-dependent Cadherin mechanosensing regulates efficient epithelial barrier formation. Biol Open 1(11):1128–1140PubMedCentralPubMedCrossRefGoogle Scholar
  74. Ukropec JA, Hollinger MK et al (2000) SHP2 association with VE-cadherin complexes in human endothelial cells is regulated by thrombin. J Biol Chem 275(8):5983–5986PubMedCrossRefGoogle Scholar
  75. Valiron O, Chevrier V et al (1996) Desmoplakin expression and organization at human umbilical vein endothelial cell-to-cell junctions. J Cell Sci 109(Pt 8):2141–2149PubMedGoogle Scholar
  76. Vasioukhin V, Bauer C et al (2000) Directed actin polymerization is the driving force for epithelial cell-cell adhesion. Cell 100(2):209–219PubMedCrossRefGoogle Scholar
  77. Vega FM, Fruhwirth G et al (2011) RhoA and RhoC have distinct roles in migration and invasion by acting through different targets. J Cell Biol 193(4):655–665PubMedCentralPubMedCrossRefGoogle Scholar
  78. Vestweber D, Broermann A et al (2010) Control of endothelial barrier function by regulating vascular endothelial-cadherin. Curr Opin Hematol 17(3):230–236PubMedCrossRefGoogle Scholar
  79. Wang S, Cao C et al (2012) Pericytes regulate vascular basement membrane remodeling and govern neutrophil extravasation during inflammation. PLoS ONE 7(9):e45499PubMedCentralPubMedCrossRefGoogle Scholar
  80. Wildenberg GA, Dohn MR et al (2006) p120-catenin and p190RhoGAP regulate cell-cell adhesion by coordinating antagonism between Rac and Rho. Cell 127(5):1027–1039PubMedCrossRefGoogle Scholar
  81. Wilson CW, Parker LH, et al (2013) Rasip1 regulates vertebrate vascular endothelial junction stability through Epac1-Rap1 signaling. Blood 122:3678–3690Google Scholar
  82. Wojciak-Stothard B, Ridley AJ (2002) Rho GTPases and the regulation of endothelial permeability. Vascul Pharmacol 39(4–5):187–199PubMedCrossRefGoogle Scholar
  83. Wong EY, Morgan L et al (2000) Vascular endothelial growth factor stimulates dephosphorylation of the catenins p120 and p100 in endothelial cells. Biochem J 346(Pt 1):209–216PubMedCentralPubMedCrossRefGoogle Scholar
  84. Worthylake RA, Burridge K (2003) RhoA and ROCK promote migration by limiting membrane protrusions. J Biol Chem 278(15):13578–13584PubMedCrossRefGoogle Scholar
  85. Yamamoto T, Harada N et al (1999) In vivo interaction of AF-6 with activated Ras and ZO-1. Biochem Biophys Res Commun 259(1):103–107PubMedCrossRefGoogle Scholar
  86. Yokoyama S, Tachibana K et al (2001) alpha-catenin-independent recruitment of ZO-1 to nectin-based cell-cell adhesion sites through afadin. Mol Biol Cell 12(6):1595–1609PubMedCentralPubMedCrossRefGoogle Scholar
  87. Yonemura S, Wada Y et al (2010) alpha-Catenin as a tension transducer that induces adherens junction development. Nat Cell Biol 12(6):533–542PubMedCrossRefGoogle Scholar
  88. Zebda N, Dubrovskyi O et al (2012) Focal adhesion kinase regulation of mechanotransduction and its impact on endothelial cell functions. Microvasc Res 83(1):71–81PubMedCentralPubMedCrossRefGoogle Scholar
  89. Zhang Z, Izaguirre G et al (2004) The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreading. Mol Biol Cell 15(9):4234–4247PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Hubrecht Institute for Developmental Biology and Stem Cell ResearchUniversity Medical Centre UtrechtUtrechtThe Netherlands

Personalised recommendations