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Angiopoietins

  • Yvonne ReissEmail author
Chapter
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 180)

Abstract

The formation of new blood vessels plays an important role during the development and progression of a disease. In recent years, there has been a tremendous effort to uncover the molecular mechanisms that drive blood vessel growth in adult tissues. Angiopoietins belong to a family of growth factors that are critically involved in blood vessel formation during developmental and pathological angiogenesis. The importance of Angiopoietin signaling has been recognized in transgenic mouse models as the genetic ablation of Ang-1, and its primary receptor Tie2 has led to early embryonic lethality. Interesting and unusual for a family of ligands, Ang-2 has been identified as an antagonist of Ang-1 in endothelial cells as evidenced by a similar embryonic phenotype when Ang-2 was overexpressed in transgenic mice. In this review, we focus on the functional consequences of autocrine Angiopoietin signaling in endothelial cells.

Keywords

Vascular Endothelial Growth Factor Tumor Vessel Pathological Angiogenesis Inhibit Tumor Angiogenesis Pericyte Coverage 
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.

Notes

Acknowledgment

I gratefully acknowledge Jutta Reiss for helping with the illustrations and cartoons, and Andrea Tal for confocal images. This work is supported by the SFB/TR23 – C1 and the Excellence Cluster Cardio-Pulmonary System (ECCPS).

References

  1. Carmeliet P, Ferreira V, Breier G et al (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380:435–439CrossRefPubMedGoogle Scholar
  2. Ferrara N, Carver-Moore K, Chen H et al (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380:439–442CrossRefPubMedGoogle Scholar
  3. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676CrossRefPubMedGoogle Scholar
  4. Conway EM, Collen D, Carmeliet P (2001) Molecular mechanisms of blood vessel growth. Cardiovasc Res 49:507–521CrossRefPubMedGoogle Scholar
  5. Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674CrossRefPubMedGoogle Scholar
  6. Suri C, McClain J, Thurston G et al (1998) Increased vascularization in mice overexpressing angiopoietin-1. Science 282:468–471CrossRefPubMedGoogle Scholar
  7. Maisonpierre PC, Suri C, Jones PF et al (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60CrossRefPubMedGoogle Scholar
  8. Brindle NP, Saharinen P, Alitalo K (2006) Signaling and functions of angiopoietin-1 in vascular protection. Circ Res 98:1014–1023CrossRefPubMedGoogle Scholar
  9. Hanahan D (1997) Signaling vascular morphogenesis and maintenance. Science 277:48–50CrossRefPubMedGoogle Scholar
  10. Davis S, Aldrich TH, Jones PF et al (1996) Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87:1161–1169CrossRefPubMedGoogle Scholar
  11. Valenzuela DM, Griffiths JA, Rojas J et al (1999) Angiopoietins 3 and 4: diverging gene counterparts in mice and humans. Proc Natl Acad Sci U S A 96:1904–1909CrossRefPubMedGoogle Scholar
  12. Sato TN, Tozawa Y, Deutsch U et al (1995) Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376:70–74CrossRefPubMedGoogle Scholar
  13. Dumont DJ, Fong GH, Puri MC, Gradwohl G, Alitalo K, Breitman ML (1995) Vascularization of the mouse embryo: a study of flk-1, tek, tie, and vascular endothelial growth factor expression during development. Dev Dyn 203:80–92PubMedGoogle Scholar
  14. Barton WA, Tzvetkova-Robev D, Miranda EP et al (2006) Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex. Nat Struct Mol Biol 13:524–532CrossRefPubMedGoogle Scholar
  15. Fiedler U, Krissl T, Koidl S et al (2003) Angiopoietin-1 and angiopoietin-2 share the same binding domains in the Tie-2 receptor involving the first Ig-like loop and the epidermal growth factor-like repeats. J Biol Chem 278:1721–1727CrossRefPubMedGoogle Scholar
  16. Dumont DJ, Gradwohl GJ, Fong GH, Auerbach R, Breitman ML (1993) The endothelial-specific receptor tyrosine kinase, tek, is a member of a new subfamily of receptors. Oncogene 8:1293–1301PubMedGoogle Scholar
  17. Sato TN, Qin Y, Kozak CA, Audus KL (1993) Tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. Proc Natl Acad Sci U S A 90:9355–9358CrossRefPubMedGoogle Scholar
  18. Schnurch H, Risau W (1993) Expression of tie-2, a member of a novel family of receptor tyrosine kinases, in the endothelial cell lineage. Development 119:957–968PubMedGoogle Scholar
  19. Partanen J, Armstrong E, Makela TP et al (1992) A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol Cell Biol 12:1698–1707PubMedGoogle Scholar
  20. Saharinen P, Kerkela K, Ekman N et al (2005) Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J Cell Biol 169:239–243CrossRefPubMedGoogle Scholar
  21. Jones N, Master Z, Jones J et al (1999) Identification of Tek/Tie2 binding partners. Binding to a multifunctional docking site mediates cell survival and migration. J Biol Chem 274:30896–30905CrossRefPubMedGoogle Scholar
  22. Papapetropoulos A, Fulton D, Mahboubi K et al (2000) Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J Biol Chem 275:9102–9105CrossRefPubMedGoogle Scholar
  23. Audero E, Cascone I, Maniero F et al (2004) Adaptor ShcA protein binds tyrosine kinase Tie2 receptor and regulates migration and sprouting but not survival of endothelial cells. J Biol Chem 279:13224–13233CrossRefPubMedGoogle Scholar
  24. Hayes AJ, Huang WQ, Mallah J, Yang D, Lippman ME, Li LY (1999) Angiopoietin-1 and its receptor Tie-2 participate in the regulation of capillary-like tubule formation and survival of endothelial cells. Microvasc Res 58:224–237CrossRefPubMedGoogle Scholar
  25. Koblizek TI, Weiss C, Yancopoulos GD, Deutsch U, Risau W (1998) Angiopoietin-1 induces sprouting angiogenesis in vitro. Curr Biol 8:529–532CrossRefPubMedGoogle Scholar
  26. Suri C, Jones PF, Patan S et al (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87: 1171–1180CrossRefPubMedGoogle Scholar
  27. Wong AL, Haroon ZA, Werner S, Dewhirst MW, Greenberg CS, Peters KG (1997) Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. Circ Res 81:567–574PubMedGoogle Scholar
  28. Saharinen P, Eklund L, Miettinen J et al (2008) Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat Cell Biol 10:527–537CrossRefPubMedGoogle Scholar
  29. Fukuhara S, Sako K, Minami T et al (2008) Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. Nat Cell Biol 10:513–526CrossRefPubMedGoogle Scholar
  30. Reiss Y, Droste J, Heil M et al (2007) Angiopoietin-2 impairs revascularization after limb ischemia. Circ Res 101(1):88–96CrossRefPubMedGoogle Scholar
  31. Scharpfenecker M, Fiedler U, Reiss Y, Augustin HG (2005) The Tie-2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism. J Cell Sci 118:771–780CrossRefPubMedGoogle Scholar
  32. Holash J, Maisonpierre PC, Compton D et al (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284:1994–1998CrossRefPubMedGoogle Scholar
  33. Stratmann A, Risau W, Plate KH (1998) Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am J Pathol 153:1459–1466PubMedGoogle Scholar
  34. Gale NW, Thurston G, Hackett SF et al (2002) Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev Cell 3:411–423CrossRefPubMedGoogle Scholar
  35. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186CrossRefPubMedGoogle Scholar
  36. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364CrossRefPubMedGoogle Scholar
  37. Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248CrossRefPubMedGoogle Scholar
  38. Reiss Y, Machein MR, Plate KH (2005) The role of angiopoietins during angiogenesis in gliomas. Brain Pathol 15:311–317CrossRefPubMedGoogle Scholar
  39. Tait CR, Jones PF (2004) Angiopoietins in tumours: the angiogenic switch. J Pathol 204:1–10CrossRefPubMedGoogle Scholar
  40. Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160:985–1000PubMedGoogle Scholar
  41. Ward NL, Dumont DJ (2002) The angiopoietins and Tie2/Tek: adding to the complexity of cardiovascular development. Semin Cell Dev Biol 13:19–27CrossRefPubMedGoogle Scholar
  42. Stoeltzing O, Ahmad SA, Liu W et al (2003) Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors. Cancer Res 63:3370–3377PubMedGoogle Scholar
  43. Hawighorst T, Skobe M, Streit M et al (2002) Activation of the tie2 receptor by angiopoietin-1 enhances tumor vessel maturation and impairs squamous cell carcinoma growth. Am J Pathol 160:1381–1392PubMedGoogle Scholar
  44. Tian S, Hayes AJ, Metheny-Barlow LJ, Li LY (2002) Stabilization of breast cancer xenograft tumour neovasculature by angiopoietin-1. Br J Cancer 86:645–651CrossRefPubMedGoogle Scholar
  45. Stoeltzing O, Ahmad SA, Liu W et al (2002) Angiopoietin-1 inhibits tumour growth and ascites formation in a murine model of peritoneal carcinomatosis. Br J Cancer 87:1182–1187CrossRefPubMedGoogle Scholar
  46. Ahmad SA, Liu W, Jung YD et al (2001) The effects of angiopoietin-1 and -2 on tumor growth and angiogenesis in human colon cancer. Cancer Res 61:1255–1259PubMedGoogle Scholar
  47. Yu Q, Stamenkovic I (2001) Angiopoietin-2 is implicated in the regulation of tumor angiogenesis. Am J Pathol 158:563–570PubMedGoogle Scholar
  48. Hayes AJ, Huang WQ, Yu J et al (2000) Expression and function of angiopoietin-1 in breast cancer. Br J Cancer 83:1154–1160CrossRefPubMedGoogle Scholar
  49. Shim WS, Teh M, Bapna A et al (2002) Angiopoietin 1 promotes tumor angiogenesis and tumor vessel plasticity of human cervical cancer in mice. Exp Cell Res 279:299–309CrossRefPubMedGoogle Scholar
  50. Machein MR, Knedla A, Knoth R, Wagner S, Neuschl E, Plate KH (2004) Angiopoietin-1 promotes tumor angiogenesis in a rat glioma model. Am J Pathol 165:1557–1570PubMedGoogle Scholar
  51. Cao Y, Sonveaux P, Liu S et al (2007) Systemic overexpression of angiopoietin-2 promotes tumor microvessel regression and inhibits angiogenesis and tumor growth. Cancer Res 67:3835–3844CrossRefPubMedGoogle Scholar
  52. Zhang L, Yang N, Park JW et al (2003) Tumor-derived vascular endothelial growth factor up-regulates angiopoietin-2 in host endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian cancer. Cancer Res 63:3403–3412PubMedGoogle Scholar
  53. Hu B, Guo P, Fang Q et al (2003) Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2. Proc Natl Acad Sci U S A 100:8904–8909CrossRefPubMedGoogle Scholar
  54. Etoh T, Inoue H, Tanaka S, Barnard GF, Kitano S, Mori M (2001) Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. Cancer Res 61:2145–2153PubMedGoogle Scholar
  55. Tanaka S, Mori M, Sakamoto Y, Makuuchi M, Sugimachi K, Wands JR (1999) Biologic significance of angiopoietin-2 expression in human hepatocellular carcinoma. J Clin Invest 103:341–345CrossRefPubMedGoogle Scholar
  56. Hashizume H, Baluk P, Morikawa S et al (2000) Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 156:1363–1380PubMedGoogle Scholar
  57. Hegen A, Koidl S, Weindel K, Marme D, Augustin HG, Fiedler U (2004) Expression of angiopoietin-2 in endothelial cells is controlled by positive and negative regulatory promoter elements. Arterioscler Thromb Vasc Biol 24:1803–1809CrossRefPubMedGoogle Scholar
  58. Ochiumi T, Tanaka S, Oka S et al (2004) Clinical significance of angiopoietin-2 expression at the deepest invasive tumor site of advanced colorectal carcinoma. Int J Oncol 24:539–547PubMedGoogle Scholar
  59. Sfiligoi C, de Luca A, Cascone I et al (2003) Angiopoietin-2 expression in breast cancer correlates with lymph node invasion and short survival. Int J Cancer 103:466–474CrossRefPubMedGoogle Scholar
  60. Siemeister G, Schirner M, Weindel K et al (1999) Two independent mechanisms essential for tumor angiogenesis: inhibition of human melanoma xenograft growth by interfering with either the vascular endothelial growth factor receptor pathway or the Tie-2 pathway. Cancer Res 59:3185–3191PubMedGoogle Scholar
  61. Lin P, Buxton JA, Acheson A et al (1998) Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2. Proc Natl Acad Sci U S A 95:8829–8834CrossRefPubMedGoogle Scholar
  62. Lin P, Polverini P, Dewhirst M, Shan S, Rao PS, Peters K (1997) Inhibition of tumor angiogenesis using a soluble receptor establishes a role for Tie2 in pathologic vascular growth. J Clin Invest 100:2072–2078CrossRefPubMedGoogle Scholar
  63. Oliner J, Min H, Leal J et al (2004) Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6:507–516CrossRefPubMedGoogle Scholar
  64. McDonald DM, Thurston G, Baluk P (1999) Endothelial gaps as sites for plasma leakage in inflammation. Microcirculation 6:7–22PubMedGoogle Scholar
  65. Gamble JR, Drew J, Trezise L et al (2000) Angiopoietin-1 is an antipermeability and anti-inflammatory agent in vitro and targets cell junctions. Circ Res 87:603–607PubMedGoogle Scholar
  66. Wang Y, Pampou S, Fujikawa K, Varticovski L (2004) Opposing effect of angiopoietin-1 on VEGF-mediated disruption of endothelial cell-cell interactions requires activation of PKC beta. J Cell Physiol 198:53–61CrossRefPubMedGoogle Scholar
  67. Gavard J, Patel V, Gutkind JS (2008) Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Dev Cell 14:25–36CrossRefPubMedGoogle Scholar
  68. Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8:618–631CrossRefPubMedGoogle Scholar
  69. Grunewald M, Avraham I, Dor Y et al (2006) VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124:175–189CrossRefPubMedGoogle Scholar
  70. De Palma M, Murdoch C, Venneri MA, Naldini L, Lewis CE (2007) Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends Immunol 28:519–524CrossRefPubMedGoogle Scholar
  71. De Palma M, Venneri MA, Roca C, Naldini L (2003) Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat Med 9: 789–795CrossRefPubMedGoogle Scholar
  72. De Palma M, Venneri MA, Galli R et al (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8: 211–226CrossRefPubMedGoogle Scholar
  73. Machein MR, Renninger S, de Lima-Hahn E, Plate KH (2003) Minor contribution of bone marrow-derived endothelial progenitors to the vascularization of murine gliomas. Brain Pathol 13:582–597CrossRefPubMedGoogle Scholar
  74. Fiedler U, Reiss Y, Scharpfenecker M et al (2006) Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 12:235–239CrossRefPubMedGoogle Scholar
  75. Winkler F, Kozin SV, Tong RT et al (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553–563PubMedGoogle Scholar
  76. De Palma M, Mazzieri R, Politi LS et al (2008) Tumor-targeted interferon-alpha delivery by Tie2- expressing monocytes inhibits tumor growth and metastasis. Cancer Cell 14:299–311CrossRefPubMedGoogle Scholar
  77. Thurston G, Suri C, Smith K et al (1999) Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286:2511–2514CrossRefPubMedGoogle Scholar
  78. Puri MC, Rossant J, Alitalo K, Bernstein A, Partanen J (1995) The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells. EMBO J 14:5884–5891PubMedGoogle Scholar
  79. Puri MC, Partanen J, Rossant J, Bernstein A (1999) Interaction of the TEK and TIE receptor tyrosine kinases during cardiovascular development. Development 126:4569–4580PubMedGoogle Scholar
  80. Dumont DJ, Gradwohl G, Fong GH et al (1994) Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev 8:1897–1909CrossRefPubMedGoogle Scholar
  81. Puri MC, Bernstein A (2003) Requirement for the TIE family of receptor tyrosine kinases in adult but not fetal hematopoiesis. Proc Natl Acad Sci U S A 100:12753–12758CrossRefPubMedGoogle Scholar
  82. Reiss Y, Knedla A, Tal AO et al (2009) Switching of vascular phenotypes within a murine breast cancer model induced by Angiopoietin-2. J Path 217 (4):571–580CrossRefPubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Institute of Neurology/Edinger InstituteFrankfurt University Medical SchoolFrankfurtGermany

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