, Volume 5, Issue 1–2, pp 1–9 | Cite as

Wnt signaling in the vasculature

  • A.M. Goodwin
  • P.A. D'Amore


The Wnt signaling pathway regulates normal development as well as a variety of pathologies. Studies of the Wnt pathway have focused largely on very early development and on tumorigenesis. Recent observations point to a role for Wnt signaling in vessel development and pathology. Although not yet investigated systematically, several Wnt ligands have been demonstrated to be expressed in the cells of blood vessels in vivo and in vitro, including Wnt-2, -5a, -7a and -10b. Mice deficient for Wnt-2 display vascular abnormalities including defective placental vasculature. Wnt receptors, called frizzled (Fz), are also expressed by vascular cells in culture and in situ. Of the 10 murine Fz identified to date, Fz-1, -2, -3, and -5 have been demonstrated in endothelial and vascular smooth muscle cells; mice deficient for Fz-5 display vascular abnormalities and are embryonic lethal. Two soluble, naturally occurring Wnt antagonists, frizzled-related proteins (FRP)-1 and -3, are also expressed by vascular cells. Stabilization of the downstream signaling component β-catenin in blood vessels has been demonstrated in several developmental and pathologic states, further supporting the idea that Wnt signaling plays an important regulatory role in the vasculature.

angiogenesis β-catenin endostatin frizzled frizzled-related protein intimal hyperplasia 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Orsulic S, Peifer M. Cell-cell signalling: Wingless lands at last. Curr Biol 1996; 6: 1363–7.Google Scholar
  2. 2.
    Dale TC. Signal transduction by the Wnt family of ligands. Biochem J 1998; 329: 209–23.Google Scholar
  3. 3.
    Miller JR. The Wnts. Genome Biol 2001; 3: 1–15.Google Scholar
  4. 4.
    Moon RT, Brown JD, Yang-Snyder JA, Miller JR. Structurally related receptors and antagonists compete for secreted Wnt ligands. Cell 1997; 88: 725–8.Google Scholar
  5. 5.
    Zorn AM. Wnt signalling: Antagonistic Dickkopfs. Curr Biol 2001; 11: R592–5.Google Scholar
  6. 6.
    Hsieh JC, Kodjabachian L, Rebbert ML et al. A new secreted protein that binds to Wnt proteins and inhibits their activities. Nature 1999; 398: 431–6.Google Scholar
  7. 7.
    Piccolo S, Agius E, Leyns L et al. The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature 1999; 397: 707–10.Google Scholar
  8. 8.
    Uusitalo M, Heikkila M, Vainio S. Molecular genetic studies of Wnt signaling in the mouse. Exp Cell Res 1999; 253: 336–48.Google Scholar
  9. 9.
    Schneider VA, Mercola M. Wnt antagonism initiates cardiogenesis in Xenopus laevis. Genes Dev 2001; 15: 304–15.Google Scholar
  10. 10.
    Marvin MJ, Di Rocco G, Gardiner A et al. Inhibition of Wnt activity induces heart formation from posterior mesoderm. Genes Dev 2001; 15: 316–27.Google Scholar
  11. 11.
    Pandur P, Läsche M, Eisenberg LM, Kühl M. Wnt-11 activation of a non-canonical Wnt signalling pathway is required for cardiogenesis. Nature 2002; 418: 636–41.Google Scholar
  12. 12.
    Van Den Berg DJ, Sharma AK, Bruno E, Hoffman R. Role of members of the Wnt gene family in human hematopoiesis. Blood 1998; 92: 3189–202.Google Scholar
  13. 13.
    Brandon C, Eisenberg LM, Eisenberg CA. WNT signaling modulates the diversification of hematopoiet ic cells. Blood 2000; 96: 4132–41.Google Scholar
  14. 14.
    Yamane T, Kunisada T, Tsukamoto H et al. Wnt signaling regulates hemopoiesis through stromal cells. J Immunol 2001; 167: 765–72.Google Scholar
  15. 15.
    Morin PJ. Beta-catenin signaling and cancer. Bioessays 1999; 21: 1021–30.Google Scholar
  16. 16.
    Polakis P. Wnt signaling and cancer. Genes Dev 2000; 14: 1837–51.Google Scholar
  17. 17.
    Smalley MJ, Dale TC. Wnt signalling in mammalian development and cancer. Cancer Metastasis Rev 1999; 18: 215–30.Google Scholar
  18. 18.
    Sen M, Lauterbach K, El-Gabalawy H et al. Expression and function of wingless and frizzled homologs in rheumatoid arthritis. Proc Natl Acad Sci USA 2000; 97: 2791–6.Google Scholar
  19. 19.
    Sen M, Chamorro M, Reifert J et al. Blockade of Wnt-5A/frizzled 5 signaling inhibits rheumatoid synoviocyte activation. Arthritis Rheum 2001; 44: 772–81.Google Scholar
  20. 20.
    De Ferrari GV, Inestrosa NC. Wnt signaling function in Alzheimer's disease. Brain Res Brain Res Rev 2000; 33: 1–12.Google Scholar
  21. 21.
    Darland DC, D'Amore PA. Cell-cell interactions in vascular development. Curr Top Dev Biol 2001; 52: 107–49.Google Scholar
  22. 22.
    Dimmeler S, Zeiher AM. Endothelial cell apoptosis in angiogenesis and vessel regression. Circ Res 2000; 87: 434–9.Google Scholar
  23. 23.
    Nör JE, Polverini PJ. Role of endothel ial cell survival and death signals in angiogenesis. Angiogenesis 1999; 3: 101–16.Google Scholar
  24. 24.
    Fisher SA, Langille BL, Srivastava D. Apoptosis during cardiovascular development. Circ Res 2000; 87: 856–64.Google Scholar
  25. 25.
    Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1: 27–31.Google Scholar
  26. 26.
    Newby AC, Zaltsman AB. Molecular mechanisms in intimal hyperplasia. J Pathol 2000; 190: 300–9.Google Scholar
  27. 27.
    Wright M, Aikawa M, Szeto W, Papkoff J. Identification of a Wnt-responsive signal transduction pathway in primary endothelial cells. Biochem Biophys Res Commun 1999; 263: 384–8.Google Scholar
  28. 28.
    Monkley SJ, Delaney SJ, Pennisi DJ et al. Targeted disruption of the Wnt2 gene results in placentation defects. Development 1996; 122: 3343–53.Google Scholar
  29. 29.
    Ishikawa T, Tamai Y, Zorn AM et al. Mouse Wnt receptor gene Fzd5 is essential for yolk sac and placental angiogenesis. Development 2001; 128: 25–33.Google Scholar
  30. 30.
    Chen S, Guttridge DC, You Z et al. Wnt-1 signaling inhibits apoptosis by activating beta-catenin/T cell factor-mediated transcription. J Cell Biol 2001; 152: 87–96.Google Scholar
  31. 31.
    Mao C, Malek OT, Pueyo ME et al. Differential expression of rat frizzled-related frzb-1 and frizzled receptor fz1 and fz2 genes in the rat aorta after balloon injury. Arterioscler Thromb Vasc Biol 2000; 20: 43–51.Google Scholar
  32. 32.
    Sala CF, Formenti E, Terstappen GC, Caricasole A. Identification, gene structure, and expression of human frizzled-3 (FZD3). Biochem Biophys Res Commun 2000; 273: 27–34.Google Scholar
  33. 33.
    Chan SD, Karpf DB, Fowlkes ME et al. Two homologs of the Drosophila polarity gene frizzled (fz) are widely expressed in mammalian tissues. J Biol Chem 1992; 267: 25202–7.Google Scholar
  34. 34.
    van Gijn ME, Blankesteijn WM, Smits JF et al. Frizzled 2 is transiently expressed in neural crest-containing areas during development of the heart and great arteries in the mouse. Anat Embryol (Berl) 2001; 203: 185–92.Google Scholar
  35. 35.
    Blankesteijn WM, Essers-Janssen YP, Verluyten MJ et al. A homologue of Drosophila tissue polarity gene frizzled is expressed in migrating myofibroblasts in the infarcted rat heart. Nat Med 1997; 3: 541–4.Google Scholar
  36. 36.
    Gazit A, Yaniv A, Bafico A et al. Human frizzled 1 interacts with transforming Wnts to transduce a TCF dependent transcriptional response. Oncogene 1999; 18: 5959–66.Google Scholar
  37. 37.
    He X, Saint-Jeannet JP, Wang Y et al. A member of the Frizzled protein family mediating axis induction by Wnt-5A. Science 1997; 275: 1652–4.Google Scholar
  38. 38.
    Wang Y, Huso D, Cahill H et al. Progressive cerebellar, auditory, and esophageal dysfunction caused by targeted disruption of the frizzled-4 gene. J Neurosci 2001; 21: 461–71.Google Scholar
  39. 39.
    Robitaille J, MacDonald ML, Kaykas A et al. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet (in press).Google Scholar
  40. 40.
    Jaspard B, Couffinhal T, Dufourcq P et al. Expression pattern of mouse sFRP-1 and mWnt-8 gene during heart morphogenesis. Mech Dev 2000; 90: 263–7.Google Scholar
  41. 41.
    Duplàa C, Jaspard B, Moreau C, D'Amore PA. Identification and cloning of a secreted protein related to the cysteine-rich domain of frizzled: Evidence for a role in endothelial cell growth control. Circ Res 1999; 84: 1433–45.Google Scholar
  42. 42.
    Dennis S, Aikawa M, Szeto W et al. A secreted frizzled related protein, FrzA, selectively associates with Wnt-1 protein and regulates Wnt-1 signaling. J Cell Sci 1999; 112: 3815–20.Google Scholar
  43. 43.
    Bafico A, Gazit A, Pramila T et al. Interaction off rizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling. J Biol Chem 1999; 274: 16180–7.Google Scholar
  44. 44.
    Finch PW, He X, Kelley MJ et al. Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action. Proc Natl Acad Sci USA 1997; 94: 6770–5.Google Scholar
  45. 45.
    Xu Q, D'Amore PA, Sokol SY. Functional and biochemical interactions of Wnts with FrzA, a secreted Wnt antagonist. Development 1998; 125: 4767–76.Google Scholar
  46. 46.
    Melkonyan HS, Chang WC, Shapiro JP et al. SARPs: A family of secreted apoptosis-related proteins. Proc Natl Acad Sci USA 1997; 94: 13636–41.Google Scholar
  47. 47.
    Mayr T, Deutsch U, Kuhl M et al. Fritz: A secreted frizzled related protein that inhibits Wnt activity. Mech Dev 1997; 63: 109–25.Google Scholar
  48. 48.
    Schumann H, Holtz J, Zerkowski HR, Hatzfeld M. Expression of secreted frizzled related proteins 3 and 4 in human ventricular myocardium correlates with apoptosis related gene expression. Cardiovasc Res 2000; 45: 720–8.Google Scholar
  49. 49.
    Wang S, Krinks M, Lin K et al. Frzb, a secreted protein expressed in the Spemann organizer, binds and inhibits Wnt-8. Cell 1997; 88: 757–66.Google Scholar
  50. 50.
    Wang S, Krinks M, Moos M Jr. Frzb-1, an antagonist of Wnt-1 and Wnt-8, does not block signaling by Wnts-3A,-5A, or-11. Biochem Biophys Res Commun 1997; 236: 502–4.Google Scholar
  51. 51.
    Eberhart CG, Tihan T, Burger PC. Nuclear localization and mutation of beta-catenin in medulloblastomas. J Neuropathol Exp Neurol 2000; 59: 333–7.Google Scholar
  52. 52.
    Eberhart CG, Argani P. Wnt signaling in human development: Beta-catenin nuclear translocation in fetal lung, kidney, placenta, capillaries, adrenal, and cartilage. Pediatr Dev Pathol 2001; 4: 351–7.Google Scholar
  53. 53.
    Blankesteijn WM, van Gijn ME, Essers-Janssen YP et al. Betacatenin, an inducer of uncontrolled cell proliferation and migration in malignancies, is localized in the cytoplasm of vascular endothelium during neovascularization after myocardial infarction. Am J Pathol 2000; 157: 877–83.Google Scholar
  54. 54.
    Yano H, Hara A, Shinoda J et al. Immunohistochemical analysis of beta-catenin in N-ethyl-N-nitrosourea-induced rat gliomas: Implications in regulation of angiogen esis. Neurol Res 2000; 22: 527–32.Google Scholar
  55. 55.
    Yano H, Hara A, Takenaka K et al. Differential expression of beta-catenin in human glioblastoma multiforme and normal brain tissue. Neurol Res 2000; 22: 650–6.Google Scholar
  56. 56.
    Wang X, Xiao Y, Mou Y et al. A role for the beta-catenin/T-cell factor signaling cascade in vascular remodeling. Circ Res 2002; 90: 340–7.Google Scholar
  57. 57.
    van der Heyden MA, Rook MB, Hermans MM et al. Identification of connexin43 as a functional target for Wnt signalling. J Cell Sci 1998; 111: 1741–9.Google Scholar
  58. 58.
    Ai Z, Fischer A, Spray DC et al. Wnt-1 regulation of connex in43 in cardiac myocytes. J Clin Invest 2000; 105: 161–71.Google Scholar
  59. 59.
    Kwak BR, Pepper MS, Gros DB, Meda P. Inhibition of endothelial wound repair by dominant negative connexin inhibitors. Mol Biol Cell 2001; 12: 831–45.Google Scholar
  60. 60.
    Gabriels JE, Paul DL. Connexin43 is highly localized to sites of disturbed flow in rat aortic endothelium but connexin37 and connexin40 are more uniformly distributed. Circ Res 1998; 83: 636–43.Google Scholar
  61. 61.
    Yeh HI, Lai YJ, Chang HM et al. Multiple connexin expression in regenerating arterial endothelial gap junctions. Arterioscler Thromb Vasc Biol 2000; 20: 1753–62.Google Scholar
  62. 62.
    Moses MA. The regulation ofneovasculari zation of matrix metalloproteinases and their inhibitors. Stem Cells 1997; 15: 180–9.Google Scholar
  63. 63.
    Brabletz T, Jung A, Dag S et al. Beta-catenin regulates the expression ofthe matrix metalloproteinase-7 in human colorectal cancer. Am J Pathol 1999; 155: 1033–8.Google Scholar
  64. 64.
    Crawford HC, Fingleton BM, Rudolph-Owen LA et al. The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors. Oncogene 1999; 18: 2883–91.Google Scholar
  65. 65.
    Huo N, Ichikawa Y, Kamiyama M et al. MMP-7 (matrilysin) accelerated growth ofhuman umbilical vein endothelial cells. Cancer Lett 2002; 177: 95–100.Google Scholar
  66. 66.
    Gradl D, Kuhl M, Wedlich D. The Wnt/Wg signal transducer bcatenin controls fibronectin expression. Mol Cell Biol 1999; 19: 5576–87.Google Scholar
  67. 67.
    Thyberg J, Blomgren K, Roy J, Tran PK, Hedin U. Phenotypic modulation of smooth muscle cells after arterial injury is associated with changes in the distribution of laminin and fibronectin. J Histochem Cytochem 1997; 45: 837–46.Google Scholar
  68. 68.
    Roy J, Tran PK, Religa P et al. Fibronectin promotes cell cycle entry in smooth muscle cells in primary culture. Exp Cell Res 2002; 273: 169–77.Google Scholar
  69. 69.
    Roberts JM. Evolving ideas about cyclins. Cell 1999; 98: 129–32.Google Scholar
  70. 70.
    Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999; 398: 422–6.Google Scholar
  71. 71.
    Shtutman M, Zhurinsky J, Simcha I et al. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA 1999; 96: 5522–7.Google Scholar
  72. 72.
    He TC, Sparks AB, Rago C et al. Identification ofc-MYC as a target ofthe APC pathway. Science 1998; 281: 1509–12.Google Scholar
  73. 73.
    Hilker M, Tellmann G, Buerke M et al. Expression of the protooncogene c-myc in human stenotic aortocoronary bypass grafts. Pathol Res Pract 2001; 197: 811–6.Google Scholar
  74. 74.
    Ngo CV, Gee M, Akhtar N et al. An in vivo function for the transforming Myc protein: Elicitation of the angiogenic phenotype. Cell Growth Differ 2000; 11: 201–10.Google Scholar
  75. 75.
    Howe LR, Subbaramaiah K, Chung WJ et al. Transcriptional activation of cyclooxygenase-2 in Wnt-1–transformed mouse mammary epithelial cells. Cancer Res 1999; 59: 1572–7.Google Scholar
  76. 76.
    Gately S. The contributions ofcyclooxygenase-2 to tumor angiogenesis. Cancer Metastasis Rev 2000; 19: 19–27.Google Scholar
  77. 77.
    Zhang X, Gaspard JP, Chung DC. Regulation of vascular endothelial growth factor by the Wnt and k-ras pathways in colonic neoplasia. Cancer Res 2001; 61: 6050–4.Google Scholar
  78. 78.
    Ferrara N. Role ofvascular endothelial growth factor in regulation of physiologica l angiogenesis. Am J Physiol Cell Physiol 2001; 280: C1358–66.Google Scholar
  79. 79.
    Kühl M, Sheldahl LC, Park M et al. The Wnt/Ca2+ pathway: A new vertebrate Wnt signaling pathway takes shape. Trends Genet 2000; 16: 279–83.Google Scholar
  80. 80.
    Boutros M, Mlodzik M. Dishevelled: At the crossroads of divergent intracellular signaling pathways. Mech Dev 1999; 83: 27–37.Google Scholar
  81. 81.
    Weston CR, Davis RJ. The JNK signal transduction pathway. Curr Opin Genet Dev 2002; 12: 14–21.Google Scholar
  82. 82.
    Cossu G, Borello U. Wnt signaling and the activation of myogenesis in mammals. EMBO J 1999; 18: 6867–72.Google Scholar
  83. 83.
    Kwan H, Pecenka V, Tsukamoto A et al. Transgenes expressing the Wnt-1 and int-2 proto-oncogenes cooperate during mammary carcinogenesis in doubly transgenic mice. Mol Cell Biol 1992; 12: 147–54.Google Scholar
  84. 84.
    Capdevila J, Izpisua Belmonte JC. Patterning mechanisms controlling vertebrate limb development. Annu Rev Cell Dev Biol 2001; 17: 87–132.Google Scholar
  85. 85.
    Manoukian AS, Woodgett JR. Role ofglycogen synthase kinase-3 in cancer: Regulation by Wnts and other signaling pathways. Adv Cancer Res 2002; 84: 203–29.Google Scholar
  86. 86.
    Conacci-Sorrell M, Zhurinsky J, Ben-Ze'ev A. The cadherin-catenin adhesion system in signaling and cancer. J Clin Invest 2002; 109: 987–91.Google Scholar
  87. 87.
    Stambolic V. PTEN: A new twist on beta-catenin? Trends Pharmacol Sci 2002; 23: 104–6.Google Scholar
  88. 88.
    Labbé E, Letamendia A, Attisano L. Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-beta and Wnt pathways. Proc Natl Acad Sci USA 2000; 97: 8358–63.Google Scholar
  89. 89.
    Letamendia A, Labbé E, Attisano L. Transcriptional regulation by Smads: crosstalk between the TGF-beta and Wnt pathways. J Bone Joint Surg Am 2001; 83–A: S31–9.Google Scholar
  90. 90.
    Nishita M, Hashimoto MK, Ogata S et al. Interaction between Wnt and TGF-beta signalling pathways during formation of Spemann's organizer. Nature 2000; 403: 781–5.Google Scholar
  91. 91.
    Smalley MJ, Dale TC. Wnt signaling and mammary tumorigenesis. J Mammary Gland Biol Neoplasia 2001; 6: 37–52.Google Scholar
  92. 92.
    Vainio SJ, Uusitalo MS. A road to kidney tubules via the Wnt pathway. Pediatr Nephrol 2000; 15: 151–6.Google Scholar
  93. 93.
    Lin Y, Liu A, Zhang S et al. Induction of ureter branching as a response to Wnt-2b signaling during early kidney organogenesis. Dev Dyn 2001; 222: 26–39.Google Scholar
  94. 94.
    Uyttendaele H, Soriano JV, Montesano R, Kitajewski J. Notch4 and Wnt-1 proteins function to regulate branching morphogenesis of mammary epithelial cells in an opposing fashion. Dev Biol 1998; 196: 204–17.Google Scholar
  95. 95.
    Leong KG, Hu X, Li L et al. Activated Notch4 inhibits angiogenesis: Role of beta 1–integrin activation. Mol Cell Biol 2002; 22: 2830–41.Google Scholar
  96. 96.
    O'Reilly M, Boehm T, Shing Y et al. Endostatin: An endogenous inhibitor ofangiogenesi s and tumor growth. Cell 1997; 88: 277–5.Google Scholar
  97. 97.
    Sim BK, MacDonald NJ, Gubish ER. Angiostatin and endostatin: Endogenous inhibitors oftumor growth. Cancer Metastasis Rev 2000; 19: 181–90.Google Scholar
  98. 98.
    Shichiri M, Hirata Y. Antiangiogenesis signals by endostatin. FASEB J 2001; 15: 1044–153.Google Scholar
  99. 99.
    Hanai JI, Dhanabal M, Karumanchi SA et al. Endostatin causes G1 arrest of endothelial cells through inhibition of Cyclin D1. J Biol Chem 2002; 277: 16464–9.Google Scholar
  100. 100.
    Hanai JI, Gloy J, Karumanchi SA et al. Endostatin is a potential inhibitor of Wnt signaling. J Cell Biol 2002; 158: 529–39.Google Scholar
  101. 101.
    Venkiteswaran K, Xiao K, Summers S et al. Regulation of endothelial barrier function and growth by VE-cadherin, plakoglobin, and beta-catenin. Am J Physiol Cell Physiol 2002; 283: C811–21.Google Scholar
  102. 102.
    Shu W, Jiang YQ, Lu MM, Morrisey EE. Wnt7b regulates mesenchymal proliferation and vascular development in the lung. Development 2002; 129: 4831–42.Google Scholar
  103. 103.
    Parr BA, Cornish VA, Cybulsky MI, McMahon AP. Wnt7b regulates placental development in mice. Dev Biol 2001; 237: 324–32.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • A.M. Goodwin
    • 1
  • P.A. D'Amore
    • 1
  1. 1.The Schepens Eye Research Institute and the Department of OphthalmologyHarvard Medical SchoolBostonUSA

Personalised recommendations