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The role of the Angiopoietins in vascular morphogenesis

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Abstracts

The Angiopoietin/Tie system acts as a vascular specific ligand/receptor system to control endothelial cell survival and vascular maturation. The Angiopoietin family includes four ligands (Angiopoietin-1, Angiopoietin-2 and Angiopoietin-3/4) and two corresponding tyrosine kinase receptors (Tie1 and Tie2). Ang-1 and Ang-2 are specific ligands of Tie2 binding the receptor with similar affinity. Tie2 activation promotes vessel assembly and maturation by mediating survival signals for endothelial cells and regulating the recruitment of mural cells. Ang-1 acts in a paracrine agonistic manner inducing Tie2 phosphorylation and subsequent vessel stabilization. In contrast, Ang-2 is produced by endothelial cells and acts as an autocrine antagonist of Ang-1-mediated Tie2 activation. Ang-2 thereby primes the vascular endothelium to exogenous cytokines and induces vascular destabilization at higher concentrations. Ang-2 is strongly expressed in the vasculature of many tumors and it has been suggested that Ang-2 may act synergistically with other cytokines such as vascular endothelial growth factor to promote tumor-associated angiogenesis and tumor progression. The better mechanistic understanding of the Ang/Tie system is gradually paving the way toward the rationale exploitation of this vascular signaling system as a therapeutic target for neoplastic and non-neoplastic diseases.

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References

  1. 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 87:1161–1169. doi:10.1016/S0092-8674(00)81812-7

    PubMed  CAS  Google Scholar 

  2. Maisonpierre PC, Suri C, Jones PF et al (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60. doi:10.1126/science.277.5322.55

    PubMed  CAS  Google Scholar 

  3. Kim I, Kwak HJ, Ahn JE et al (1999) Molecular cloning and characterization of a novel angiopoietin family protein, angiopoietin-3. FEBS Lett 443:353–356. doi:10.1016/S0014-5793(99)00008-3

    PubMed  CAS  Google Scholar 

  4. Nishimura M, Miki T, Yashima R et al (1999) Angiopoietin-3, a novel member of the angiopoietin family. FEBS Lett 448:254–256. doi:10.1016/S0014-5793(99)00381-6

    PubMed  CAS  Google Scholar 

  5. Valenzuela DM, Griffiths JA, Rojas J et al (1999) Angiopoietins 3 and 4: diverging gene counterparts in mice and humans. Proc Natl Acad Sci USA 96:1904–1909. doi:10.1073/pnas.96.5.1904

    PubMed  CAS  Google Scholar 

  6. Kim KT, Choi HH, Steinmetz MO et al (2005) Oligomerization and multimerization are critical for angiopoietin-1 to bind and phosphorylate Tie2. J Biol Chem 280:20126–20131. doi:10.1074/jbc.M500292200

    PubMed  CAS  Google Scholar 

  7. Procopio WN, Pelavin PI, Lee WM et al (1999) Angiopoietin-1 and -2 coiled coil domains mediate distinct homo-oligomerization patterns, but fibrinogen-like domains mediate ligand activity. J Biol Chem 274:30196–30201. doi:10.1074/jbc.274.42.30196

    PubMed  CAS  Google Scholar 

  8. 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 278:1721–1727. doi:10.1074/jbc.M208550200

    PubMed  CAS  Google Scholar 

  9. Huang YQ, Li JJ, Karpatkin S (2000) Identification of a family of alternatively spliced mRNA species of angiopoietin-1. Blood 95:1993–1999

    PubMed  CAS  Google Scholar 

  10. Mezquita J, Mezquita B, Pau M et al (1999) Characterization of a novel form of angiopoietin-2 (Ang-2B) and expression of VEGF and angiopoietin-2 during chicken testicular development and regression. Biochem Biophys Res Commun 260:492–498. doi:10.1006/bbrc.1999.0934

    PubMed  CAS  Google Scholar 

  11. Kim I, Kim JH, Ryu YS et al (2000) Characterization and expression of a novel alternatively spliced human angiopoietin-2. J Biol Chem 275:18550–18556. doi:10.1074/jbc.M910084199

    PubMed  CAS  Google Scholar 

  12. Kim I, Kim JH, Moon SO et al (2000) Angiopoietin-2 at high concentration can enhance endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Oncogene 19:4549–4552. doi:10.1038/sj.onc.1203800

    PubMed  CAS  Google Scholar 

  13. Teichert-Kuliszewska K, Maisonpierre PC, Jones N et al (2001) Biological action of angiopoietin-2 in a fibrin matrix model of angiogenesis is associated with activation of Tie2. Cardiovasc Res 49:659–670. doi:10.1016/S0008-6363(00)00231-5

    PubMed  CAS  Google Scholar 

  14. Daly C, Pasnikowski E, Burova E et al (2006) Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells. Proc Natl Acad Sci USA 103:15491–15496. doi:10.1073/pnas.0607538103

    PubMed  CAS  Google Scholar 

  15. Fiedler U, Scharpfenecker M, Koidl S et al (2004) The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood 103:4150–4156. doi:10.1182/blood-2003-10-3685

    PubMed  CAS  Google Scholar 

  16. Scharpfenecker M, Fiedler U, Reiss Y et al (2005) The Tie-2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism. J Cell Sci 118:771–780. doi:10.1242/jcs.01653

    PubMed  CAS  Google Scholar 

  17. Oh H, Takagi H, Suzuma K et al (1999) Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem 274:15732–15739. doi:10.1074/jbc.274.22.15732

    PubMed  CAS  Google Scholar 

  18. Kim I, Kim JH, Ryu YS et al (2000) Tumor necrosis factor-alpha upregulates angiopoietin-2 in human umbilical vein endothelial cells. Biochem Biophys Res Commun 269:361–365. doi:10.1006/bbrc.2000.2296

    PubMed  CAS  Google Scholar 

  19. Huang YQ, Li JJ, Hu L et al (2002) Thrombin induces increased expression and secretion of angiopoietin-2 from human umbilical vein endothelial cells. Blood 99:1646–1650. doi:10.1182/blood.V99.5.1646

    PubMed  CAS  Google Scholar 

  20. Pichiule P, Chavez JC, LaManna JC (2004) Hypoxic regulation of angiopoietin-2 expression in endothelial cells. J Biol Chem 279:12171–12180. doi:10.1074/jbc.M305146200

    PubMed  CAS  Google Scholar 

  21. Goede V, Schmidt T, Kimmina S et al (1998) Analysis of blood vessel maturation processes during cyclic ovarian angiogenesis. Lab Invest 78:1385–1394

    PubMed  CAS  Google Scholar 

  22. Zagzag D, Hooper A, Friedlander DR et al (1999) In situ expression of angiopoietins in astrocytomas identifies angiopoietin-2 as an early marker of tumor angiogenesis. Exp Neurol 159:391–400. doi:10.1006/exnr.1999.7162

    PubMed  CAS  Google Scholar 

  23. 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 63:3403–3412

    PubMed  CAS  Google Scholar 

  24. Oliner J, Min H, Leal J et al (2004) Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6:507–516. doi:10.1016/j.ccr.2004.09.030

    PubMed  CAS  Google Scholar 

  25. Tanaka S, Mori M, Sakamoto Y et al (1999) Biologic significance of angiopoietin-2 expression in human hepatocellular carcinoma. J Clin Invest 103:341–345. doi:10.1172/JCI4891

    PubMed  CAS  Google Scholar 

  26. Koga K, Todaka T, Morioka M et al (2001) Expression of angiopoietin-2 in human glioma cells and its role for angiogenesis. Cancer Res 61:6248–6254

    PubMed  CAS  Google Scholar 

  27. Torimura T, Ueno T, Kin M et al (2004) Overexpression of angiopoietin-1 and angiopoietin-2 in hepatocellular carcinoma. J Hepatol 40:799–807. doi:10.1016/j.jhep.2004.01.027

    PubMed  CAS  Google Scholar 

  28. Hackett SF, Ozaki H, Strauss RW et al (2000) Angiopoietin 2 expression in the retina: upregulation during physiologic and pathologic neovascularization. J Cell Physiol 184:275–284. doi:10.1002/1097-4652(200009)184:3<275::AID-JCP1>3.0.CO;2-7

    PubMed  CAS  Google Scholar 

  29. Yao D, Taguchi T, Matsumura T et al (2007) High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A. J Biol Chem 282:31038–31045. doi:10.1074/jbc.M704703200

    PubMed  CAS  Google Scholar 

  30. Suri C, Jones PF, Patan S et al (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87:1171–1180. doi:10.1016/S0092-8674(00)81813-9

    PubMed  CAS  Google Scholar 

  31. 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 3:411–423. doi:10.1016/S1534-5807(02)00217-4

    PubMed  CAS  Google Scholar 

  32. 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 153:1459–1466

    PubMed  CAS  Google Scholar 

  33. 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 119:957–968

    PubMed  CAS  Google Scholar 

  34. Macdonald PR, Progias P, Ciani B et al (2006) Structure of the extracellular domain of Tie receptor tyrosine kinases and localization of the angiopoietin-binding epitope. J Biol Chem 281:28408–28414. doi:10.1074/jbc.M605219200

    PubMed  CAS  Google Scholar 

  35. Korhonen J, Polvi A, Partanen J et al (1994) The mouse tie receptor tyrosine kinase gene: expression during embryonic angiogenesis. Oncogene 9:395–403

    PubMed  CAS  Google Scholar 

  36. Marron MB, Hughes DP, Edge MD et al (2000) Evidence for heterotypic interaction between the receptor tyrosine kinases TIE-1 and TIE-2. J Biol Chem 275:39741–39746. doi:10.1074/jbc.M007189200

    PubMed  CAS  Google Scholar 

  37. Tsiamis AC, Morris PN, Marron MB et al (2002) Vascular endothelial growth factor modulates the Tie-2:Tie-1 receptor complex. Microvasc Res 63:149–158. doi:10.1006/mvre.2001.2377

    PubMed  CAS  Google Scholar 

  38. Marron MB, Singh H, Tahir TA et al (2007) Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor-tyrosine kinase Tie2. J Biol Chem 282:30509–30517. doi:10.1074/jbc.M702535200

    PubMed  CAS  Google Scholar 

  39. Yabkowitz R, Meyer S, Yanagihara D et al (1997) Regulation of tie receptor expression on human endothelial cells by protein kinase C-mediated release of soluble tie. Blood 90:706–715

    PubMed  CAS  Google Scholar 

  40. Yabkowitz R, Meyer S, Black T et al (1999) Inflammatory cytokines and vascular endothelial growth factor stimulate the release of soluble tie receptor from human endothelial cells via metalloprotease activation. Blood 93:1969–1979

    PubMed  CAS  Google Scholar 

  41. Chen-Konak L, Guetta-Shubin Y, Yahav H et al (2003) Transcriptional and post-translation regulation of the Tie1 receptor by fluid shear stress changes in vascular endothelial cells. FASEB J 17:2121–2123

    PubMed  CAS  Google Scholar 

  42. 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 169:239–243. doi:10.1083/jcb.200411105

    PubMed  CAS  Google Scholar 

  43. Dumont DJ, Yamaguchi TP, Conlon RA et al (1992) Tek, a novel tyrosine kinase gene located on mouse chromosome 4, is expressed in endothelial cells and their presumptive precursors. Oncogene 7:1471–1480

    PubMed  CAS  Google Scholar 

  44. 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 376:70–74. doi:10.1038/376070a0

    PubMed  CAS  Google Scholar 

  45. Brown LF, Dezube BJ, Tognazzi K et al (2000) Expression of Tie1, Tie2, and angiopoietins 1, 2, and 4 in Kaposi’s sarcoma and cutaneous angiosarcoma. Am J Pathol 156:2179–2183

    PubMed  CAS  Google Scholar 

  46. Helfrich I, Edler L, Sucker A et al (2009) Angiopoietin-2 levels are associated with disease progression in metastatic malignant melanoma. Clin Cancer Res 15:1384–1392. doi:10.1158/1078-0432.CCR-08-1615

    PubMed  CAS  Google Scholar 

  47. 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 8:211–226. doi:10.1016/j.ccr.2005.08.002

    PubMed  Google Scholar 

  48. Wong AL, Haroon ZA, Werner S et al (1997) Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. Circ Res 81:567–574

    PubMed  CAS  Google Scholar 

  49. Peters KG, Coogan A, Berry D et al (1998) Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis. Br J Cancer 77:51–56

    PubMed  CAS  Google Scholar 

  50. Takahama M, Tsutsumi M, Tsujiuchi T et al (1999) Enhanced expression of Tie2, its ligand angiopoietin-1, vascular endothelial growth factor, and CD31 in human non-small cell lung carcinomas. Clin Cancer Res 5:2506–2510

    PubMed  CAS  Google Scholar 

  51. 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 8:1897–1909. doi:10.1101/gad.8.16.1897

    PubMed  CAS  Google Scholar 

  52. Patan S (1998) TIE1 and TIE2 receptor tyrosine kinases inversely regulate embryonic angiogenesis by the mechanism of intussusceptive microvascular growth. Microvasc Res 56:1–21. doi:10.1006/mvre.1998.2081

    PubMed  CAS  Google Scholar 

  53. Takakura N, Huang XL, Naruse T et al (1998) Critical role of the TIE2 endothelial cell receptor in the development of definitive hematopoiesis. Immunity 9:677–686. doi:10.1016/S1074-7613(00)80665-2

    PubMed  CAS  Google Scholar 

  54. Jones N, Voskas D, Master Z et al (2001) Rescue of the early vascular defects in Tek/Tie2 null mice reveals an essential survival function. EMBO Rep 2:438–445

    PubMed  CAS  Google Scholar 

  55. Takagi H, Koyama S, Seike H et al (2003) Potential role of the angiopoietin/tie2 system in ischemia-induced retinal neovascularization. Invest Ophthalmol Vis Sci 44:393–402. doi:10.1167/iovs.02-0276

    PubMed  Google Scholar 

  56. Reusch P, Barleon B, Weindel K et al (2001) Identification of a soluble form of the angiopoietin receptor TIE-2 released from endothelial cells and present in human blood. Angiogenesis 4:123–131. doi:10.1023/A:1012226627813

    PubMed  CAS  Google Scholar 

  57. Chung NA, Makin AJ, Lip GY (2003) Measurement of the soluble angiopoietin receptor tie-2 in patients with coronary artery disease: development and application of an immunoassay. Eur J Clin Invest 33:529–535. doi:10.1046/j.1365-2362.2003.01173.x

    PubMed  CAS  Google Scholar 

  58. Vikkula M, Boon LM, Carraway KL 3rd et al (1996) Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 87:1181–1190. doi:10.1016/S0092-8674(00)81814-0

    PubMed  CAS  Google Scholar 

  59. Rodewald HR, Sato TN (1996) Tie1, a receptor tyrosine kinase essential for vascular endothelial cell integrity, is not critical for the development of hematopoietic cells. Oncogene 12:397–404

    PubMed  CAS  Google Scholar 

  60. Puri MC, Partanen J, Rossant J et al (1999) Interaction of the TEK and TIE receptor tyrosine kinases during cardiovascular development. Development 126:4569–4580

    PubMed  CAS  Google Scholar 

  61. Ward NL, Van Slyke P, Sturk C et al (2004) Angiopoietin 1 expression levels in the myocardium direct coronary vessel development. Dev Dyn 229:500–509. doi:10.1002/dvdy.10479

    PubMed  CAS  Google Scholar 

  62. Suri C, McClain J, Thurston G et al (1998) Increased vascularization in mice overexpressing angiopoietin-1. Science 282:468–471. doi:10.1126/science.282.5388.468

    PubMed  CAS  Google Scholar 

  63. Reiss Y, Droste J, Heil M, Tribulova S et al (2007) Angiopoietin-2 impairs revascularization after limb ischemia. Circ Res 101:88–96. doi:10.1161/CIRCRESAHA.106.143594

    PubMed  CAS  Google Scholar 

  64. Hammes HP, Lin J, Wagner P et al (2004) Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy. Diabetes 53:1104–1110. doi:10.2337/diabetes.53.4.1104

    PubMed  CAS  Google Scholar 

  65. Holash J, Maisonpierre PC, SJ ComptonD et al (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284:1994–1998

    PubMed  CAS  Google Scholar 

  66. Lobov IB, Brooks PC, Lang RA (2002) Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci USA 99:11205–11210. doi:10.1073/pnas.172161899

    PubMed  CAS  Google Scholar 

  67. Korff T, Kimmina S, Martiny-Baron G et al (2001) Blood vessel maturation in a 3-dimensional spheroidal coculture model: direct contact with smooth muscle cells regulates endothelial cell quiescence and abrogates VEGF responsiveness. FASEB J 15:447–457. doi:10.1096/fj.00-0139com

    PubMed  CAS  Google Scholar 

  68. 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 12:235–239. doi:10.1038/nm1351

    PubMed  CAS  Google Scholar 

  69. Shimoda H, Bernas MJ, Witte MH et al (2007) Abnormal recruitment of periendothelial cells to lymphatic capillaries in digestive organs of angiopoietin-2-deficient mice. Cell Tissue Res 328:329–337. doi:10.1007/s00441-006-0360-8

    PubMed  CAS  Google Scholar 

  70. Hackett SF, Wiegand S, Yancopoulos G et al (2002) Angiopoietin-2 plays an important role in retinal angiogenesis. J Cell Physiol 192:182–187. doi:10.1002/jcp.10128

    PubMed  CAS  Google Scholar 

  71. Dumont DJ, Gradwohl GJ, Fong GH et al (1993) The endothelial-specific receptor tyrosine kinase, tek, is a member of a new subfamily of receptors. Oncogene 8:1293–1301

    PubMed  CAS  Google Scholar 

  72. Kim I, Kim HG, So JN et al (2000) Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3’-Kinase/Akt signal transduction pathway. Circ Res 86:24–29

    PubMed  CAS  Google Scholar 

  73. Jones N, Iljin K, Dumont DJ et al (2001) Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol 2:257–267. doi:10.1038/35067005

    PubMed  CAS  Google Scholar 

  74. Hodous BL, Geuns-Meyer SD, Hughes PE et al (2007) Evolution of a highly selective and potent 2-(pyridin-2-yl)-1, 3, 5-triazine Tie-2 kinase inhibitor. J Med Chem 50:611–626. doi:10.1021/jm061107l

    PubMed  CAS  Google Scholar 

  75. Semones M, Feng Y, Johnson N et al (2007) Pyridinylimidazole inhibitors of Tie2 kinase. Bioorg Med Chem Lett 17:4756–4760. doi:10.1016/j.bmcl.2007.06.068

    PubMed  CAS  Google Scholar 

  76. Cardone MH, Roy N, Stennicke HR et al (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321. doi:10.1126/science.282.5392.1318

    PubMed  CAS  Google Scholar 

  77. Papapetropoulos FultonD, Mahboubi KA et al (2000) Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J Biol Chem 275:9102–9105. doi:10.1074/jbc.275.13.9102

    PubMed  CAS  Google Scholar 

  78. Harfouche R, Hassessian HM, Guo Y et al (2002) Mechanisms which mediate the antiapoptotic effects of angiopoietin-1 on endothelial cells. Microvasc Res 64:135–147. doi:10.1006/mvre.2002.2421

    PubMed  CAS  Google Scholar 

  79. Iivanainen E, Nelimarkka L, Elenius V et al (2003) Angiopoietin-regulated recruitment of vascular smooth muscle cells by endothelial-derived heparin binding EGF-like growth factor. FASEB J 17:1609–1621. doi:10.1096/fj.02-0939com

    PubMed  CAS  Google Scholar 

  80. Kobayashi H, DeBusk LM, Babichev YO et al (2006) Hepatocyte growth factor mediates angiopoietin-induced smooth muscle cell recruitment. Blood 108:1260–1266. doi:10.1182/blood-2005-09-012807

    PubMed  CAS  Google Scholar 

  81. Lindahl P, Johansson BR, Leveen P et al (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–245. doi:10.1126/science.277.5323.242

    PubMed  CAS  Google Scholar 

  82. Hellstrom M, Kalen M, Lindahl P et al (1999) Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126:3047–3055

    PubMed  CAS  Google Scholar 

  83. Uemura A et al (2002) Recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells. J Clin Invest 110:1619–1628

    PubMed  CAS  Google Scholar 

  84. Hirschi KK, Rohovsky SA, D’Amore PA (1998) PDGF, TGF-beta, and heterotypic cell–cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate. J Cell Biol 141:805–814. doi:10.1083/jcb.141.3.805

    PubMed  CAS  Google Scholar 

  85. Oh SP, Seki T, Goss KA et al (2000) Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci USA 97:2626–2631. doi:10.1073/pnas.97.6.2626

    PubMed  CAS  Google Scholar 

  86. Nishishita T, Lin PC (2004) Angiopoietin 1, PDGF-B, and TGF-beta gene regulation in endothelial cell and smooth muscle cell interaction. J Cell Biochem 91:584–593. doi:10.1002/jcb.10718

    PubMed  CAS  Google Scholar 

  87. Kidoya H, Ueno M, Yamada Y et al (2008) Spatial and temporal role of the apelin/APJ system in the caliber size regulation of blood vessels during angiogenesis. EMBO J 27:522–534. doi:10.1038/sj.emboj.7601982

    PubMed  CAS  Google Scholar 

  88. 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 10:513–526. doi:10.1038/ncb1714

    PubMed  CAS  Google Scholar 

  89. 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 10:527–537. doi:10.1038/ncb1715

    PubMed  CAS  Google Scholar 

  90. Jones N, Dumont DJ (1998) The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R. Oncogene 17:1097–1108. doi:10.1038/sj.onc.1202115

    PubMed  CAS  Google Scholar 

  91. Gavard J, Gutkind JS (2006) VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 8:1223–1234. doi:10.1038/ncb1486

    PubMed  CAS  Google Scholar 

  92. Dejana E, Orsenigo F, Lampugnani MG (2008) The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 121:2115–2122. doi:10.1242/jcs.017897

    PubMed  CAS  Google Scholar 

  93. Gavard J, Patel V, Gutkind JS (2008) Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Dev Cell 14:25–36. doi:10.1016/j.devcel.2007.10.019

    PubMed  CAS  Google Scholar 

  94. Li X, Hahn CN, Parsons M et al (2004) Role of protein kinase Czeta in thrombin-induced endothelial permeability changes: inhibition by angiopoietin-1. Blood 104:1716–1724. doi:10.1182/blood-2003-11-3744

    PubMed  CAS  Google Scholar 

  95. Li X, Stankovic M, Bonder CS et al (2008) Basal and angiopoietin-1-mediated endothelial permeability is regulated by sphingosine kinase-1. Blood 111:3489–3497. doi:10.1182/blood-2007-05-092148

    PubMed  CAS  Google Scholar 

  96. Huang L, Turck CW, Rao P et al (1995) GRB2 and SH-PTP2: potentially important endothelial signaling molecules downstream of the TEK/TIE2 receptor tyrosine kinase. Oncogene 11:2097–2103

    PubMed  CAS  Google Scholar 

  97. Kontos CD, Stauffer TP, Yang WP et al (1998) Tyrosine 1101 of Tie2 is the major site of association of p85 and is required for activation of phosphatidylinositol 3-kinase and Akt. Mol Cell Biol 18:4131–4140

    PubMed  CAS  Google Scholar 

  98. Peters KG, Kontos CD, Lin PC et al (2004) Functional significance of Tie2 signaling in the adult vasculature. Recent Prog Horm Res 59:51–71. doi:10.1210/rp.59.1.51

    PubMed  CAS  Google Scholar 

  99. Fujikawa K, de Aos Scherpenseel I, Jain SK et al (1999) Role of PI 3-kinase in angiopoietin-1-mediated migration and attachment-dependent survival of endothelial cells. Exp Cell Res 253:663–672. doi:10.1006/excr.1999.4693

    PubMed  CAS  Google Scholar 

  100. Kim I, Oh JL, Ryu YS et al (2002) Angiopoietin-1 negatively regulates expression and activity of tissue factor in endothelial cells. FASEB J 16:126–128

    PubMed  Google Scholar 

  101. Zhu WH, Nicosia RF (2002) The thin prep rat aortic ring assay: a modified method for the characterization of angiogenesis in whole mounts. Angiogenesis 5:81–86. doi:10.1023/A:1021509004829

    PubMed  CAS  Google Scholar 

  102. Jones N, Chen SH, Sturk C et al (2003) A unique autophosphorylation site on Tie2/Tek mediates Dok-R phosphotyrosine binding domain binding and function. Mol Cell Biol 23:2658–2668. doi:10.1128/MCB.23.8.2658-2668.2003

    PubMed  CAS  Google Scholar 

  103. Kim I, Kim HG, Moon SO et al (2000) Angiopoietin-1 induces endothelial cell sprouting through the activation of focal adhesion kinase and plasmin secretion. Circ Res 86:952–959

    PubMed  CAS  Google Scholar 

  104. Tournaire R, Simon MP, le Noble F et al (2004) A short synthetic peptide inhibits signal transduction, migration and angiogenesis mediated by Tie2 receptor. EMBO Rep 5:262–267. doi:10.1038/sj.embor.7400100

    PubMed  CAS  Google Scholar 

  105. Witzenbichler B, Westermann D, Knueppel S et al (2005) Protective role of angiopoietin-1 in endotoxic shock. Circulation 111:97–105. doi:10.1161/01.CIR.0000151287.08202.8E

    PubMed  CAS  Google Scholar 

  106. Kim I, Moon SO, Park SK et al (2001) Angiopoietin-1 reduces VEGF-stimulated leukocyte adhesion to endothelial cells by reducing ICAM-1, VCAM-1, and E-selectin expression. Circ Res 89:477–479. doi:10.1161/hh1801.097034

    PubMed  CAS  Google Scholar 

  107. Nykanen AI, Krebs R, Saaristo A et al (2003) Angiopoietin-1 protects against the development of cardiac allograft arteriosclerosis. Circulation 107:1308–1314. doi:10.1161/01.CIR.0000054623.35669.3F

    PubMed  Google Scholar 

  108. Cho CH, Kammerer RA, Lee HJ et al (2004) Designed angiopoietin-1 variant, COMP-Ang1, protects against radiation-induced endothelial cell apoptosis. Proc Natl Acad Sci USA 101:5553–5558. doi:10.1073/pnas.0307575101

    PubMed  CAS  Google Scholar 

  109. Hughes DP, Marron MB, Brindle NP (2003) The antiinflammatory endothelial tyrosine kinase Tie2 interacts with a novel nuclear factor-kappaB inhibitor ABIN-2. Circ Res 92:630–636. doi:10.1161/01.RES.0000063422.38690.DC

    PubMed  CAS  Google Scholar 

  110. Jeon BH, Khanday F, Deshpande S et al (2003) Tie-ing the antiinflammatory effect of angiopoietin-1 to inhibition of NF-kappaB. Circ Res 92:586–588. doi:10.1161/01.RES.0000066881.04116.45

    PubMed  CAS  Google Scholar 

  111. Tadros A, Hughes DP, Dunmore BJ et al (2003) ABIN-2 protects endothelial cells from death and has a role in the antiapoptotic effect of angiopoietin-1. Blood 102:4407–4409. doi:10.1182/blood-2003-05-1602

    PubMed  CAS  Google Scholar 

  112. Gravallese EM, Pettit AR, Lee R et al (2003) Angiopoietin-1 is expressed in the synovium of patients with rheumatoid arthritis and is induced by tumour necrosis factor alpha. Ann Rheum Dis 62:100–107. doi:10.1136/ard.62.2.100

    PubMed  CAS  Google Scholar 

  113. Scott BB, Zaratin PF, Gilmartin AG et al (2005) TNF-alpha modulates angiopoietin-1 expression in rheumatoid synovial fibroblasts via the NF-kappa B signalling pathway. Biochem Biophys Res Commun 328:409–414. doi:10.1016/j.bbrc.2004.12.180

    PubMed  CAS  Google Scholar 

  114. Grall F, Gu X, Tan L et al (2003) Responses to the proinflammatory cytokines interleukin-1 and tumor necrosis factor alpha in cells derived from rheumatoid synovium and other joint tissues involve nuclear factor kappaB-mediated induction of the Ets transcription factor ESE-1. Arthritis Rheum 48:1249–1260. doi:10.1002/art.10942

    PubMed  CAS  Google Scholar 

  115. Brown C, Gaspar J, Pettit A et al (2004) ESE-1 is a novel transcriptional mediator of angiopoietin-1 expression in the setting of inflammation. J Biol Chem 279:12794–12803. doi:10.1074/jbc.M308593200

    PubMed  CAS  Google Scholar 

  116. Parikh SM, Mammoto T, Schultz A et al (2006) Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med 3:e46. doi:10.1371/journal.pmed.0030046

    PubMed  Google Scholar 

  117. Gallagher DC, Parikh SM, Balonov K et al (2007) Circulating Angiopoietin 2 correlates with mortality in a surgical population with acute lung injury/adult respiratory distress syndrome. Shock 29:656–661

    Google Scholar 

  118. Orfanos SE, Kotanidou A, Glynos C et al (2007) Angiopoietin-2 is increased in severe sepsis: correlation with inflammatory mediators. Crit Care Med 35:199–206. doi:10.1097/01.CCM.0000251640.77679.D7

    PubMed  CAS  Google Scholar 

  119. Siner JM, Bhandari V, Engle KM, et al. (2009) Elevated serum Angiopoietin 2 levels are associated with increased mortality in sepsis. Shock 31:348–353

    Article  PubMed  CAS  Google Scholar 

  120. Fearon U, Griosios K, Fraser A et al (2003) Angiopoietins, growth factors, and vascular morphology in early arthritis. J Rheumatol 30:260–268

    PubMed  CAS  Google Scholar 

  121. Kuroda K, Sapadin A, Shoji T et al (2001) Altered expression of angiopoietins and Tie2 endothelium receptor in psoriasis. J Invest Dermatol 116:713–720. doi:10.1046/j.1523-1747.2001.01316.x

    PubMed  CAS  Google Scholar 

  122. Etoh T, Inoue H, Tanaka S et al (2001) Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. Cancer Res 61:2145–2153

    PubMed  CAS  Google Scholar 

  123. 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 USA 100:8904–8909. doi:10.1073/pnas.1533394100

    PubMed  CAS  Google Scholar 

  124. Mandriota SJ, Pepper MS (1998) Regulation of angiopoietin-2 mRNA levels in bovine microvascular endothelial cells by cytokines and hypoxia. Circ Res 83:852–859

    PubMed  CAS  Google Scholar 

  125. Krikun G, Schatz F, Finlay T et al (2000) Expression of angiopoietin-2 by human endometrial endothelial cells: regulation by hypoxia and inflammation. Biochem Biophys Res Commun 275:159–163. doi:10.1006/bbrc.2000.3277

    PubMed  CAS  Google Scholar 

  126. Yamakawa M, Liu LX, Date T et al (2003) Hypoxia-inducible factor-1 mediates activation of cultured vascular endothelial cells by inducing multiple angiogenic factors. Circ Res 93:664–673. doi:10.1161/01.RES.0000093984.48643.D7

    PubMed  CAS  Google Scholar 

  127. Hegen A, Koidl S, Weindel K et al (2004) Expression of angiopoietin-2 in endothelial cells is controlled by positive and negative regulatory promoter elements. Arterioscler Thromb Vasc Biol 24:1803–1809. doi:10.1161/01.ATV.0000140819.81839.0e

    PubMed  CAS  Google Scholar 

  128. Lund EL, Hog A, Olsen MW et al (2004) Differential regulation of VEGF, HIF1alpha and angiopoietin-1, -2 and -4 by hypoxia and ionizing radiation in human glioblastoma. Int J Cancer 108:833–838. doi:10.1002/ijc.11662

    PubMed  CAS  Google Scholar 

  129. Watanabe D, Takagi H, Suzuma K et al (2004) Transcription factor Ets-1 mediates ischemia- and vascular endothelial growth factor-dependent retinal neovascularization. Am J Pathol 164:1827–1835

    PubMed  CAS  Google Scholar 

  130. Goettsch W, Gryczka C, Korff T et al (2008) Flow-dependent regulation of angiopoietin-2. J Cell Physiol 214:491–503. doi:10.1002/jcp.21229

    PubMed  CAS  Google Scholar 

  131. Milkiewicz M, Uchida C, Gee E et al. (2008) Shear stress-induced Ets-1 modulates protease inhibitor expression in microvascular endothelial cells. J Cell Physiol

  132. Daly C, Wong V, Burova E et al (2004) Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1). Genes Dev 18:1060–1071. doi:10.1101/gad.1189704

    PubMed  CAS  Google Scholar 

  133. Vajkoczy P, Farhadi M, Gaumann A et al (2002) Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin-2. J Clin Invest 109:777–785

    PubMed  CAS  Google Scholar 

  134. Machein MR, Knedla A, Knoth R et al (2004) Angiopoietin-1 promotes tumor angiogenesis in a rat glioma model. Am J Pathol 165:1557–1570

    PubMed  CAS  Google Scholar 

  135. Zhou YZ, Fang XQ, Li HQ et al (2007) Role of serum angiopoietin-2 level in screening for esophageal squamous cell cancer and its precursors. Chin Med J (Engl) 120:1216–1219

    CAS  Google Scholar 

  136. Kuboki S, Shimizu H, Mitsuhashi N et al. (2008) Angiopoietin-2 levels in the hepatic vein as a useful predictor of tumor invasiveness and prognosis in human hepatocellular carcinoma. J Gastroenterol Hepatol 23:157–164

    Google Scholar 

  137. Park JH, Park KJ, Kim YS et al (2007) Serum angiopoietin-2 as a clinical marker for lung cancer. Chest 132:200–206. doi:10.1378/chest.06-2915

    PubMed  CAS  Google Scholar 

  138. Ahmad SA, Liu W, Jung YD et al (2001) Differential expression of angiopoietin-1 and angiopoietin-2 in colon carcinoma. A possible mechanism for the initiation of angiogenesis. Cancer 92:1138–1143. doi:10.1002/1097-0142(20010901)92:5<1138::AID-CNCR1431>3.0.CO;2-L

    PubMed  CAS  Google Scholar 

  139. Oka N, Yamamoto Y, Takahashi M et al (2005) Expression of angiopoietin-1 and -2, and its clinical significance in human bladder cancer. BJU Int 95:660–663. doi:10.1111/j.1464-410X.2005.05358.x

    PubMed  CAS  Google Scholar 

  140. Takanami I (2004) Overexpression of Ang-2 mRNA in non-small cell lung cancer: association with angiogenesis and poor prognosis. Oncol Rep 12:849–853

    PubMed  CAS  Google Scholar 

  141. Cai M, Zhang H, Hui R (2003) Single chain Fv antibody against angiopoietin-2 inhibits VEGF-induced endothelial cell proliferation and migration in vitro. Biochem Biophys Res Commun 309:946–951. doi:10.1016/j.bbrc.2003.08.086

    PubMed  CAS  Google Scholar 

  142. White RR, Shan S, Rusconi CP et al (2003) Inhibition of rat corneal angiogenesis by a nuclease-resistant RNA aptamer specific for angiopoietin-2. Proc Natl Acad Sci USA 100:5028–5033. doi:10.1073/pnas.0831159100

    PubMed  CAS  Google Scholar 

  143. Imanishi Y, Hu B, Jarzynka MJ et al (2007) Angiopoietin-2 stimulates breast cancer metastasis through the alpha(5)beta(1) integrin-mediated pathway. Cancer Res 67:4254–4263

    PubMed  CAS  Google Scholar 

  144. Yu Q, Stamenkovic I (2001) Angiopoietin-2 is implicated in the regulation of tumor angiogenesis. Am J Pathol 158:563–570

    PubMed  CAS  Google Scholar 

  145. 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 160:1381–1392

    PubMed  CAS  Google Scholar 

  146. Hayes AJ, Huang WQ, Yu J et al (2000) Expression and function of angiopoietin-1 in breast cancer. Br J Cancer 83:1154–1160. doi:10.1054/bjoc.2000.1437

    PubMed  CAS  Google Scholar 

  147. Stoeltzing O, Ahmad SA, Liu W et al (2003) Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors. Cancer Res 63:3370–3377

    PubMed  CAS  Google Scholar 

  148. Tian S, Hayes AJ, Metheny-Barlow LJ et al (2002) Stabilization of breast cancer xenograft tumour neovasculature by angiopoietin-1. Br J Cancer 86:645–651. doi:10.1038/sj.bjc.6600082

    PubMed  CAS  Google Scholar 

  149. Nakayama T, Yao L, Tosato G (2004) Mast cell-derived angiopoietin-1 plays a critical role in the growth of plasma cell tumors. J Clin Invest 114:1317–1325

    PubMed  CAS  Google Scholar 

  150. Shim WS, Teh M, Mack PO et al (2001) Inhibition of angiopoietin-1 expression in tumor cells by an antisense RNA approach inhibited xenograft tumor growth in immunodeficient mice. Int J Cancer 94:6–15. doi:10.1002/ijc.1428

    PubMed  CAS  Google Scholar 

  151. Carlson TR, Feng Y, Maisonpierre PC et al (2001) Direct cell adhesion to the angiopoietins mediated by integrins. J Biol Chem 276:26516–26525. doi:10.1074/jbc.M100282200

    PubMed  CAS  Google Scholar 

  152. Hu B, Jarzynka MJ, Guo P et al (2006) Angiopoietin 2 induces glioma cell invasion by stimulating matrix metalloprotease 2 expression through the alphavbeta1 integrin and focal adhesion kinase signaling pathway. Cancer Res 66:775–783. doi:10.1158/0008-5472.CAN-05-1149

    PubMed  CAS  Google Scholar 

  153. Cascone I, Napione L, Maniero F et al (2005) Stable interaction between alpha5beta1 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang-1. J Cell Biol 170:993–1004. doi:10.1083/jcb.200507082

    PubMed  CAS  Google Scholar 

  154. Dallabrida SM, Ismail N, Oberle JR et al (2005) Angiopoietin-1 promotes cardiac and skeletal myocyte survival through integrins. Circ Res 96:e8–e24. doi:10.1161/01.RES.0000158285.57191.60

    PubMed  CAS  Google Scholar 

  155. Dallabrida SM, Ismail NS, Pravda EA et al (2008) Integrin binding angiopoietin-1 monomers reduce cardiac hypertrophy. FASEB J 22:3010–3023. doi:10.1096/fj.07-100966

    PubMed  CAS  Google Scholar 

  156. Ward NL, Putoczki T, Mearow K et al (2005) Vascular-specific growth factor angiopoietin 1 is involved in the organization of neuronal processes. J Comp Neurol 482:244–256. doi:10.1002/cne.20422

    PubMed  CAS  Google Scholar 

  157. Valable S, Bellail A, Lesne S et al (2003) Angiopoietin-1-induced PI3-kinase activation prevents neuronal apoptosis. FASEB J 17:443–445

    PubMed  CAS  Google Scholar 

  158. Arai F, Hirao A, Ohmura M et al (2004) Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118:149–161. doi:10.1016/j.cell.2004.07.004

    PubMed  CAS  Google Scholar 

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Thomas, M., Augustin, H.G. The role of the Angiopoietins in vascular morphogenesis. Angiogenesis 12, 125–137 (2009). https://doi.org/10.1007/s10456-009-9147-3

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