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VEGF Signaling

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Signaling Pathways in Liver Diseases

Abstract

Vascular endothelial growth factor (VEGF) is the main growth factor for angiogenesis and vasculogenesis. Identified as a vascular endothelial cell mitogen and survival factor, it has been sequenced and cloned by Ferrara and Connolly in 1989 [1, 2]. Intense research over the past years has deciphered the gene, molecular pathways, receptors, and functions of this angiogenic factor [3]. VEGF plays a key role in liver regeneration, hepatic fibrogenesis, portal hypertension, hepatocarcinogenesis, and malignant ascites formation.

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References

  1. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309

    Article  PubMed  CAS  Google Scholar 

  2. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246: 1309–1312

    Article  PubMed  CAS  Google Scholar 

  3. Ferrara N (2002) VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2:795–803

    Article  PubMed  CAS  Google Scholar 

  4. Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25

    Article  PubMed  CAS  Google Scholar 

  5. Gerber HP, Dixit V, Ferrara N (1998) Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem 273:13313–13316

    Article  PubMed  CAS  Google Scholar 

  6. Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, Ferrara N (1998) Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 273: 30336–30343

    Article  PubMed  CAS  Google Scholar 

  7. Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E (1999) Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 103:159–165

    Article  PubMed  CAS  Google Scholar 

  8. Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK (1996) Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc Natl Acad Sci U S A 93:14765–14770

    Article  PubMed  CAS  Google Scholar 

  9. Unemori EN, Ferrara N, Bauer EA, Amento EP (1992) Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 153:557–562

    Article  PubMed  CAS  Google Scholar 

  10. Zucker S, Mirza H, Conner CE, Lorenz AF, Drews MH, Bahou WF, Jesty J (1998) Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase ­production in endothelial cells: conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation. Int J Cancer 75:780–786

    Article  PubMed  CAS  Google Scholar 

  11. Pepper MS, Ferrara N, Orci L, Montesano R (1991) Vascular endothelial growth factor (VEGF) induces plasminogen ­activators and plasminogen activator inhibitor-1  in ­microvascular endothelial cells. Biochem Biophys Res Commun 181: 902–906

    Article  PubMed  CAS  Google Scholar 

  12. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985

    Article  PubMed  CAS  Google Scholar 

  13. Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146:1029–1039

    PubMed  CAS  Google Scholar 

  14. Yokomori H, Oda M, Yoshimura K, Nagai T, Ogi M, Nomura M, Ishii H (2003) Vascular endothelial growth factor increases fenestral permeability in hepatic sinusoidal endothelial cells. Liver Int 23:467–475

    Article  PubMed  CAS  Google Scholar 

  15. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M et al (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380:435–439

    Article  PubMed  CAS  Google Scholar 

  16. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea KS, Powell-Braxton L et al (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380:439–442

    Article  PubMed  CAS  Google Scholar 

  17. Matsumoto K, Yoshitomi H, Rossant J, Zaret KS (2001) Liver organogenesis promoted by endothelial cells prior to vascular function. Science 294:559–563

    Article  PubMed  CAS  Google Scholar 

  18. Fong GH, Rossant J, Gertsenstein M, Breitman ML (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376:66–70

    Article  PubMed  CAS  Google Scholar 

  19. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M,Wu XF, Breitman ML, Schuh AC (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376:62–66

    Article  PubMed  CAS  Google Scholar 

  20. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  PubMed  CAS  Google Scholar 

  21. Rafii S, Lyden D, Benezra R, Hattori K, Heissig B (2002) Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat Rev Cancer 2:826–835

    Article  PubMed  CAS  Google Scholar 

  22. Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A et al (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7: 1194–1201

    Article  PubMed  CAS  Google Scholar 

  23. de Bont ES, Guikema JE, Scherpen F, Meeuwsen T, Kamps WA, Vellenga E, Bos NA (2001) Mobilized human CD34 + hematopoietic stem cells enhance tumor growth in a nonobese diabetic/severe combined immunodeficient mouse model of human non-Hodgkin’s lymphoma. Cancer Res 61:7654–7659

    PubMed  Google Scholar 

  24. Reyes M, Dudek A, Jahagirdar B, Koodie L, Marker PH, Verfaillie CM (2002) Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 109:337–346

    PubMed  CAS  Google Scholar 

  25. Fujii H, Hirose T, Oe S, Yasuchika K, Azuma H, Fujikawa T, Nagao M et al (2002) Contribution of bone marrow cells to liver regeneration after partial hepatectomy in mice.J Hepatol 36:653–659

    Article  PubMed  CAS  Google Scholar 

  26. Jelkmann W (2001) Pitfalls in the measurement of circulating vascular endothelial growth factor. Clin Chem 47:617–623

    PubMed  CAS  Google Scholar 

  27. Webb NJ, Bottomley MJ, Watson CJ, Brenchley PE (1998) Vascular endothelial growth factor (VEGF) is released from platelets during blood clotting: implications for measurement of circulating VEGF levels in clinical disease. Clin Sci (Lond) 94:395–404

    CAS  Google Scholar 

  28. Banks RE, Forbes MA, Kinsey SE, Stanley A, Ingham E, Walters C, Selby PJ (1998) Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br J Cancer 77:956–964

    PubMed  CAS  Google Scholar 

  29. Vincenti V, Cassano C, Rocchi M, Persico G (1996) Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation 93:1493–1495

    PubMed  CAS  Google Scholar 

  30. Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA (1991) The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266:11947–11954

    PubMed  CAS  Google Scholar 

  31. Robinson CJ, Stringer SE (2001) The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 114:853–865

    PubMed  CAS  Google Scholar 

  32. Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N (1992) Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 267:26031–26037

    PubMed  CAS  Google Scholar 

  33. Plouet J, Moro F, Bertagnolli S, Coldeboeuf N, Mazarguil H, Clamens S, Bayard F (1997) Extracellular cleavage of the vascular endothelial growth factor 189-amino acid form by urokinase is required for its mitogenic effect. J Biol Chem 272:13390–13396

    Article  PubMed  CAS  Google Scholar 

  34. Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG (1991) Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A 88:9267–9271

    Article  PubMed  CAS  Google Scholar 

  35. Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y et al (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7:575–583

    Article  PubMed  CAS  Google Scholar 

  36. Olofsson B, Pajusola K, Kaipainen A, von Euler G, Joukov V, Saksela O, Orpana A et al (1996) Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci U S A 93:2576–2581

    Article  PubMed  CAS  Google Scholar 

  37. Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O et al (1996) A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. Embo J 15:1751

    PubMed  CAS  Google Scholar 

  38. Lee J, Gray A, Yuan J, Luoh SM, Avraham H, Wood WI (1996) Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. Proc Natl Acad Sci U S A 93:1988–1992

    Article  PubMed  CAS  Google Scholar 

  39. Orlandini M, Marconcini L, Ferruzzi R, Oliviero S (1996) Identification of a c-fos-induced gene that is related to the platelet-derived growth factor/vascular endothelial growth factor family. Proc Natl Acad Sci U S A 93:11675–11680

    Article  PubMed  CAS  Google Scholar 

  40. Karkkainen MJ, Makinen T, Alitalo K (2002) Lymphatic endothelium: a new frontier of metastasis research. Nat Cell Biol 4:E2–E5

    Article  CAS  Google Scholar 

  41. Farnebo F, Piehl F, Lagercrantz J (1999) Restricted expression pattern of vegf-d in the adult and fetal mouse: high expression in the embryonic lung. Biochem Biophys Res Commun 257:891–894

    Article  PubMed  CAS  Google Scholar 

  42. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M et al (1997) Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276:1423–1425

    Article  PubMed  CAS  Google Scholar 

  43. Cao R, Eriksson A, Kubo H, Alitalo K, Cao Y, Thyberg J (2004) Comparative evaluation of FGF-2-, VEGF-A-, and VEGF-C-induced angiogenesis, lymphangiogenesis, vascular fenestrations, and permeability. Circ Res 94:664–670

    Article  PubMed  CAS  Google Scholar 

  44. Lyttle DJ, Fraser KM, Fleming SB, Mercer AA, Robinson AJ (1994) Homologs of vascular endothelial growth factor are encoded by the poxvirus orf virus. J Virol 68:84–92

    PubMed  CAS  Google Scholar 

  45. Kieser A, Weich HA, Brandner G, Marme D, Kolch W (1994) Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9:963–969

    PubMed  CAS  Google Scholar 

  46. Grugel S, Finkenzeller G, Weindel K, Barleon B, Marme D (1995) Both v-Ha-Ras and v-Raf stimulate expression of the vascular endothelial growth factor in NIH 3 T3 cells.J Biol Chem 270:25915–25919

    Article  PubMed  CAS  Google Scholar 

  47. Mukhopadhyay D, Knebelmann B, Cohen HT, Ananth S, Sukhatme VP (1997) The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Mol Cell Biol 17:5629–5639

    PubMed  CAS  Google Scholar 

  48. Longo R, Sarmiento R, Fanelli M, Capaccetti B, Gattuso D, Gasparini G (2002) Anti-angiogenic therapy: rationale, challenges and clinical studies. Angiogenesis 5:237–256

    Article  PubMed  CAS  Google Scholar 

  49. Josko J, Mazurek M (2004) Transcription factors having impact on vascular endothelial growth factor (VEGF) gene expression in angiogenesis. Med Sci Monit 10: RA89–RA98

    Google Scholar 

  50. Chiang DY, Villanueva A, Hoshida Y, Peix J, Newell P, Minguez B, LeBlanc AC et al (2008) Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res 68:6779–6788

    Article  PubMed  CAS  Google Scholar 

  51. Harris AL (2002) Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47

    Article  PubMed  CAS  Google Scholar 

  52. Gerber HP, Condorelli F, Park J, Ferrara N (1997) Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem 272: 23659–23667

    Article  PubMed  CAS  Google Scholar 

  53. Dibbens JA, Miller DL, Damert A, Risau W, Vadas MA, Goodall GJ (1999) Hypoxic regulation of vascular endothelial growth factor mRNA stability requires the cooperation of multiple RNA elements. Mol Biol Cell 10:907–919

    PubMed  CAS  Google Scholar 

  54. Levy AP, Levy NS, Goldberg MA (1996) Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem 271:2746–2753

    Article  PubMed  CAS  Google Scholar 

  55. Liu LX, Lu H, Luo Y, Date T, Belanger AJ, Vincent KA, Akita GY et al (2002) Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor 1. Biochem Biophys Res Commun 291:908–914

    Article  PubMed  CAS  Google Scholar 

  56. Shima DT, Deutsch U, D’Amore PA (1995) Hypoxic induction of vascular endothelial growth factor (VEGF) in human epithelial cells is mediated by increases in mRNA stability. FEBS Lett 370:203–208

    Article  PubMed  CAS  Google Scholar 

  57. Levy NS, Chung S, Furneaux H, Levy AP (1998) Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. J Biol Chem 273: 6417–6423

    Article  PubMed  CAS  Google Scholar 

  58. Shibuya M, Yamaguchi S, Yamane A, Ikeda T, Tojo A, Matsushime H, Sato M (1990) Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene 5: 519–524

    PubMed  CAS  Google Scholar 

  59. Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy RL, Shows TB (1991) Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 6: 1677–1683

    PubMed  CAS  Google Scholar 

  60. Matthews W, Jordan CT, Gavin M, Jenkins NA, Copeland NG, Lemischka IR (1991) A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit. Proc Natl Acad Sci U S A 88:9026–9030

    Article  PubMed  CAS  Google Scholar 

  61. de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255: 989–991

    Article  PubMed  Google Scholar 

  62. Seetharam L, Gotoh N, Maru Y, Neufeld G, Yamaguchi S, Shibuya M (1995) A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. Oncogene 10:135–147

    PubMed  CAS  Google Scholar 

  63. Ross MA, Sander CM, Kleeb TB, Watkins SC, Stolz DB (2001) Spatiotemporal expression of angiogenesis growth factor receptors during the revascularization of regenerating rat liver. Hepatology 34:1135–1148

    Article  PubMed  CAS  Google Scholar 

  64. LeCouter J, Moritz DR, Li B, Phillips GL, Liang XH, Gerber HP, Hillan KJ et al (2003) Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 299:890–893

    Article  PubMed  CAS  Google Scholar 

  65. Yamane A, Seetharam L, Yamaguchi S, Gotoh N, Takahashi T, Neufeld G, Shibuya M (1994) A new communication system between hepatocytes and sinusoidal endothelial cells in liver through vascular endothelial growth factor and Flt tyrosine kinase receptor family (Flt-1 and KDR/Flk-1). Oncogene 9:2683–2690

    PubMed  CAS  Google Scholar 

  66. Mochida S, Ishikawa K, Inao M, Shibuya M, Fujiwara K (1996) Increased expressions of vascular endothelial growth factor and its receptors, flt-1 and KDR/flk-1, in regenerating rat liver. Biochem Biophys Res Commun 226:176–179

    Article  PubMed  CAS  Google Scholar 

  67. Ankoma-Sey V, Matli M, Chang KB, Lalazar A, Donner DB, Wong L, Warren RS et al (1998) Coordinated induction of VEGF receptors in mesenchymal cell types during rat hepatic wound healing. Oncogene 17:115–121

    Article  PubMed  CAS  Google Scholar 

  68. Mashiba S, Mochida S, Ishikawa K, Inao M, Matsui A, Ohno A, Ikeda H et al (1999) Inhibition of hepatic stellate cell contraction during activation in vitro by vascular endothelial growth factor in association with upregulation of FLT tyrosine kinase receptor family, FLT-1. Biochem Biophys Res Commun 258:674–678

    Article  PubMed  CAS  Google Scholar 

  69. Sawano A, Iwai S, Sakurai Y, Ito M, Shitara K, Nakahata T, Shibuya M (2001) Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood 97: 785–791

    Article  PubMed  CAS  Google Scholar 

  70. Davidson AJ, Zon LI (2003) Biomedicine: love, honor, and protect (your liver). Science 299:835–837

    Article  PubMed  CAS  Google Scholar 

  71. Nomura M, Yamagishi S, Harada S, Hayashi Y, Yamashima T, Yamashita J, Yamamoto H (1995) Possible participation of autocrine and paracrine vascular endothelial growth factors in hypoxia-induced proliferation of endothelial cells and pericytes. J Biol Chem 270:28316–28324

    Article  PubMed  CAS  Google Scholar 

  72. Couper LL, Bryant SR, Eldrup-Jorgensen J, Bredenberg CE, Lindner V (1997) Vascular endothelial growth factor increases the mitogenic response to fibroblast growth factor-2 in vascular smooth muscle cells in vivo via expression of fms-like tyrosine kinase-1. Circ Res 81: 932–939

    PubMed  CAS  Google Scholar 

  73. Sondell M, Lundborg G, Kanje M (1999) Vascular endothelial growth factor has neurotrophic activity and stimulates axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous system.J Neurosci 19:5731–5740

    PubMed  CAS  Google Scholar 

  74. Fong GH, Zhang L, Bryce DM, Peng J (1999) Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development 126:3015–3025

    PubMed  CAS  Google Scholar 

  75. Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M (1998) Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci U S A 95:9349–9354

    Article  PubMed  CAS  Google Scholar 

  76. Hiratsuka S, Maru Y, Okada A, Seiki M, Noda T, Shibuya M (2001) Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. Cancer Res 61:1207–1213

    PubMed  CAS  Google Scholar 

  77. Park JE, Chen HH, Winer J, Houck KA, Ferrara N (1994) Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 269:25646–25654

    PubMed  CAS  Google Scholar 

  78. Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH (1994) Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 269:26988–26995

    PubMed  CAS  Google Scholar 

  79. Stacker SA, Vitali A, Caesar C, Domagala T, Groenen LC, Nice E, Achen MG et al (1999) A mutant form of vascular endothelial growth factor (VEGF) that lacks VEGF receptor-2 activation retains the ability to induce vascular permeability. J Biol Chem 274:34884–34892

    Article  PubMed  CAS  Google Scholar 

  80. Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D, Kroll J et al (2003) Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 9:936–943

    Article  PubMed  CAS  Google Scholar 

  81. Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F, Nagy JA et al (2002) Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8:831–840

    PubMed  CAS  Google Scholar 

  82. Gerber HP, Malik AK, Solar GP, Sherman D, Liang XH, Meng G, Hong K et al (2002) VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417:954–958

    Article  PubMed  CAS  Google Scholar 

  83. Hiratsuka S, Nakamura K, Iwai S, Murakami M, Itoh T, Kijima H, Shipley JM et al (2002) MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2:289–300

    Article  PubMed  CAS  Google Scholar 

  84. Kendall RL, Wang G, Thomas KA (1996) Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. Biochem Biophys Res Commun 226:324–328

    Article  PubMed  CAS  Google Scholar 

  85. Barleon B, Reusch P, Totzke F, Herzog C, Keck C, Martiny-Baron G, Marme D (2001) Soluble VEGFR-1 secreted by endothelial cells and monocytes is present in human serum and plasma from healthy donors. Angiogenesis 4:143–154

    Article  PubMed  CAS  Google Scholar 

  86. Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, Bohlen P (1992) Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 187:1579–1586

    Article  PubMed  CAS  Google Scholar 

  87. Quinn TP, Peters KG, De Vries C, Ferrara N, Williams LT (1993) Fetal liver kinase 1 is a receptor for vascular ­endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Sci U S A 90: 7533–7537

    Article  PubMed  CAS  Google Scholar 

  88. Shay-Salit A, Shushy M, Wolfovitz E, Yahav H, Breviario F, Dejana E, Resnick N (2002) VEGF receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells. Proc Natl Acad Sci U S A 99:9462–9467

    Article  PubMed  CAS  Google Scholar 

  89. Pajusola K, Aprelikova O, Korhonen J, Kaipainen A, Pertovaara L, Alitalo R, Alitalo K (1992) FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines. Cancer Res 52:5738–5743

    PubMed  CAS  Google Scholar 

  90. Finnerty H, Kelleher K, Morris GE, Bean K, Merberg DM, Kriz R, Morris JC et al (1993) Molecular cloning of murine FLT and FLT4. Oncogene 8:2293–2298

    PubMed  CAS  Google Scholar 

  91. Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VW, Fang GH, Dumont D, Breitman M et al (1995) Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S A 92:3566–3570

    Article  PubMed  CAS  Google Scholar 

  92. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92:735–745

    Article  PubMed  CAS  Google Scholar 

  93. Neufeld G, Cohen T, Shraga N, Lange T, Kessler O, Herzog Y (2002) The neuropilins: multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovasc Med 12:13–19

    Article  PubMed  CAS  Google Scholar 

  94. Neufeld G, Kessler O, Herzog Y (2002) The interaction of neuropilin-1 and neuropilin-2 with tyrosine-kinase receptors for VEGF. Adv Exp Med Biol 515:81–90

    PubMed  CAS  Google Scholar 

  95. Fuh G, Li B, Crowley C, Cunningham B, Wells JA (1998) Requirements for binding and signaling of the kinase domain receptor for vascular endothelial growth factor. J Biol Chem 273:11197–11204

    Article  PubMed  CAS  Google Scholar 

  96. Matsumoto T, Claesson-Welsh L (2001) VEGF receptor signal transduction. Sci STKE 2001:RE21

    Article  Google Scholar 

  97. Eliceiri BP, Paul R, Schwartzberg PL, Hood JD, Leng J, Cheresh DA (1999) Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell 4:915–924

    Article  PubMed  CAS  Google Scholar 

  98. Guo D, Jia Q, Song HY, Warren RS, Donner DB (1995) Vascular endothelial cell growth factor promotes tyrosine phosphorylation of mediators of signal transduction that contain SH2 domains. Association with endothelial cell proliferation. J Biol Chem 270:6729–6733

    Article  PubMed  CAS  Google Scholar 

  99. Alavi A, Hood JD, Frausto R, Stupack DG, Cheresh DA (2003) Role of Raf in vascular protection from distinct apoptotic stimuli. Science 301:94–96

    Article  PubMed  CAS  Google Scholar 

  100. Gualdi R, Bossard P, Zheng M, Hamada Y, Coleman JR, Zaret KS (1996) Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev 10:1670–1682

    Article  PubMed  CAS  Google Scholar 

  101. Fabris L, Cadamuro M, Libbrecht L, Raynaud P, Spirli C, Fiorotto R, Okolicsanyi L et al (2008) Epithelial expression of angiogenic growth factors modulate arterial vasculogenesis in human liver development. Hepatology 47:719–728

    Article  PubMed  Google Scholar 

  102. Drixler TA, Vogten MJ, Ritchie ED, Van Vroonhoven TJ, Gebbink MF, Voest EE, Borel Rinkes IH (2002) Liver regeneration is an angiogenesis- associated phenomenon. Ann Surg 236:703–712

    Article  PubMed  Google Scholar 

  103. Greene AK, Wiener S, Puder M, Yoshida A, Shi B, Perez-Atayde AR, Efstathiou JA et al (2003) Endothelial-directed hepatic regeneration after partial hepatectomy. Ann Surg 237:530–535

    Article  PubMed  Google Scholar 

  104. Sato T, El-Assal ON, Ono T, Yamanoi A, Dhar DK, Nagasue N (2001) Sinusoidal endothelial cell proliferation and expression of angiopoietin/Tie family in regenerating rat liver. J Hepatol 34:690–698

    Article  PubMed  CAS  Google Scholar 

  105. Martinez-Hernandez A, Amenta PS (1995) The extracellular matrix in hepatic regeneration. Faseb J 9:1401–1410

    PubMed  CAS  Google Scholar 

  106. Redaelli CA, Semela D, Carrick FE, Ledermann M, Candinas D, Sauter B, Dufour JF (2004) Effect of vascular endothelial growth factor on functional recovery after hepatectomy in lean and obese mice. J Hepatol 40: 305–312

    Article  PubMed  CAS  Google Scholar 

  107. Taniguchi E, Sakisaka S, Matsuo K, Tanikawa K, Sata M (2001) Expression and role of vascular endothelial growth factor in liver regeneration after partial hepatectomy in rats. J Histochem Cytochem 49:121–130

    PubMed  CAS  Google Scholar 

  108. Assy N, Spira G, Paizi M, Shenkar L, Kraizer Y, Cohen T, Neufeld G et al (1999) Effect of vascular endothelial growth factor on hepatic regenerative activity following partial hepatectomy in rats. J Hepatol 30:911–915

    Article  PubMed  CAS  Google Scholar 

  109. Kalluri R, Sukhatme VP (2000) Fibrosis and angiogenesis. Curr Opin Nephrol Hypertens 9:413–418

    Article  PubMed  CAS  Google Scholar 

  110. Kalluri R (2003) Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer 3: 422–433

    Article  PubMed  CAS  Google Scholar 

  111. Yamamoto T, Kobayashi T, Phillips MJ (1984) Perinodular arteriolar plexus in liver cirrhosis. Scanning electron microscopy of microvascular casts. Liver 4:50–54

    PubMed  CAS  Google Scholar 

  112. Haratake J, Hisaoka M, Yamamoto O, Horie A (1991) Morphological changes of hepatic microcirculation in experimental rat cirrhosis: a scanning electron microscopic study. Hepatology 13:952–956

    Article  PubMed  CAS  Google Scholar 

  113. Huet PM, Goresky CA, Villeneuve JP, Marleau D, Lough JO (1982) Assessment of liver microcirculation in human cirrhosis. J Clin Invest 70:1234–1244

    Article  PubMed  CAS  Google Scholar 

  114. Villeneuve JP, Dagenais M, Huet PM, Roy A, Lapointe R, Marleau D (1996) The hepatic microcirculation in the isolated perfused human liver. Hepatology 23:24–31

    Article  PubMed  CAS  Google Scholar 

  115. Rosmorduc O, Wendum D, Corpechot C, Galy B, Sebbagh N, Raleigh J, Housset C et al (1999) Hepatocellular hypoxia-induced vascular endothelial growth factor expression and angiogenesis in experimental biliary cirrhosis. Am J Pathol 155:1065–1073

    PubMed  CAS  Google Scholar 

  116. Corpechot C, Barbu V, Wendum D, Kinnman N, Rey C, Poupon R, Housset C et al (2002) Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology 35:1010–1021

    Article  PubMed  CAS  Google Scholar 

  117. Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, Wu Y et al (2003) Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut 52:1347–1354

    Article  PubMed  CAS  Google Scholar 

  118. Wang Y, Luk J, Ikeda K, Man K, Chu A, Kaneda K, Tat Fan S (2004) Regulatory role of vHL/HIF-1alpha in hypoxia-induced VEGF production in hepatic stellate cells. Biochem Biophys Res Commun 317:358–362

    Article  PubMed  CAS  Google Scholar 

  119. Novo E, Cannito S, Zamara E, Valfre di Bonzo L, Caligiuri A, Cravanzola C, Compagnone A et al (2007) Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am J Pathol 170:1942–1953

    Article  PubMed  CAS  Google Scholar 

  120. Deleve LD, Wang X, Guo Y (2008) Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 48:920–930

    Article  PubMed  CAS  Google Scholar 

  121. Bosch J, Pizcueta P, Feu F, Fernandez M, Garcia-Pagan JC (1992) Pathophysiology of portal hypertension. Gastroen­terol Clin North Am 21:1–14

    PubMed  CAS  Google Scholar 

  122. Fernandez M, Vizzutti F, Garcia-Pagan JC, Rodes J, Bosch J (2004) Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice. Gastroenterology 126:886–894

    Article  PubMed  CAS  Google Scholar 

  123. Tugues S, Fernandez-Varo G, Munoz-Luque J, Ros J, Arroyo V, Rodes J, Friedman SL et al (2007) Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology 46:1919–1926

    Article  PubMed  CAS  Google Scholar 

  124. Fernandez M, Mejias M, Garcia-Pras E, Mendez R, Garcia-Pagan JC, Bosch J (2007) Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats. Hepatology 46:1208–1217

    Article  PubMed  CAS  Google Scholar 

  125. Lee SW, Lee YM, Bae SK, Murakami S, Yun Y, Kim KW (2000) Human hepatitis B virus X protein is a possible mediator of hypoxia-induced angiogenesis in hepatocarcinogenesis. Biochem Biophys Res Commun 268: 456–461

    Article  PubMed  CAS  Google Scholar 

  126. Yoo YG, Oh SH, Park ES, Cho H, Lee N, Park H, Kim DK et al (2003) Hepatitis B virus X protein enhances transcriptional activity of hypoxia-inducible factor-1{alpha} through activation of mitogen-activated protein kinase pathway. J Biol Chem 278:39076–39084

    Article  PubMed  CAS  Google Scholar 

  127. Moon E-J, Jeong C-H, Jeong J-W, Kim KR, Yu D-Y, Murakami S, Kim CW, et al (2004) Hepatitis B virus X protein induces angiogenesis by stabilizing hypoxia-inducible factor-1&alpha. FASEB J 18:382–4

    Google Scholar 

  128. Tao X, Shen D, Ren H, Zhang X, Zhang D, Ye J, Gu B (2000) Hepatitis B virus X protein activates expression of IGF-IR and VEGF in hepatocellular carcinoma cells. Zhonghua Gan Zang Bing Za Zhi 8:161–163

    PubMed  CAS  Google Scholar 

  129. Yan J, Chen W, Ma Y, Sun X (2000) Expression of vascular endothelial growth factor in liver tissues of hepatitis B. Zhonghua Gan Zang Bing Za Zhi 8:150–152

    PubMed  CAS  Google Scholar 

  130. Salcedo X, Medina J, Sanz-Cameno P, Garcia-Buey L, Martin-Vilchez S, Borque MJ, Lopez-Cabrera M et al (2005) The potential of angiogenesis soluble markers in chronic hepatitis C. Hepatology 42:696–701

    Article  PubMed  CAS  Google Scholar 

  131. Medina J, Caveda L, Sanz-Cameno P, Arroyo AG, Martin-Vilchez S, Majano PL, Garcia-Buey L et al (2003) Hepatocyte growth factor activates endothelial proangiogenic mechanisms relevant in chronic hepatitis C-associated neoangiogenesis. J Hepatol 38:660–667

    Article  PubMed  CAS  Google Scholar 

  132. Nasimuzzaman M, Waris G, Mikolon D, Stupack DG, Siddiqui A (2007) Hepatitis C virus stabilizes hypoxia-inducible factor 1alpha and stimulates the synthesis of vascular endothelial growth factor. J Virol 81:10249–10257

    Article  PubMed  CAS  Google Scholar 

  133. Liu C, Liu W, Yang J, Fang D (2001) HCV core protein activates expression of vascular endothelial growth factor in HepG(2) cells. Zhonghua Gan Zang Bing Za Zhi 9: 214–216

    PubMed  CAS  Google Scholar 

  134. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  135. Semenza GL (2003) Angiogenesis in ischemic and neoplastic disorders. Annu Rev Med 54:17–28

    Article  PubMed  CAS  Google Scholar 

  136. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364

    Article  PubMed  CAS  Google Scholar 

  137. Fukumura D, Xavier R, Sugiura T, Chen Y, Park EC, Lu N, Selig M et al (1998) Tumor induction of VEGF promoter activity in stromal cells. Cell 94:715–725

    Article  PubMed  CAS  Google Scholar 

  138. Jung JO, Gwak GY, Lim YS, Kim CY, Lee HS (2003) Role of hepatic stellate cells in the angiogenesis of hepatoma. Korean J Gastroenterol 42:142–148

    PubMed  Google Scholar 

  139. Park YN, Kim YB, Yang KM, Park C (2000) Increased expression of vascular endothelial growth factor and angiogenesis in the early stage of multistep hepatocarcinogenesis. Arch Pathol Lab Med 124:1061–1065

    PubMed  CAS  Google Scholar 

  140. Yamaguchi R, Yano H, Iemura A, Ogasawara S, Haramaki M, Kojiro M (1998) Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 28:68–77

    Article  PubMed  CAS  Google Scholar 

  141. Arii S, Mise M, Harada T, Furutani M, Ishigami S, Niwano M, Mizumoto M et al (1996) Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatology 24:316–322

    Article  PubMed  CAS  Google Scholar 

  142. Koga H, Sakisaka S, Ohishi M, Kawaguchi T, Taniguchi E, Sasatomi K, Harada M et al (1999) Expression of cyclooxygenase-2 in human hepatocellular carcinoma: relevance to tumor dedifferentiation. Hepatology 29:688–696

    Article  PubMed  CAS  Google Scholar 

  143. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E et al (2001) Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 35:421–430

    Article  PubMed  CAS  Google Scholar 

  144. Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, Huber J et al (2002) Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma. Hepatology 35: 834–842

    Article  PubMed  CAS  Google Scholar 

  145. Yamaguchi R, Yano H, Nakashima Y, Ogasawara S, Higaki K, Akiba J, Hicklin DJ et al (2000) Expression and localization of vascular endothelial growth factor receptors in human hepatocellular carcinoma and non-HCC tissues. Oncol Rep 7:725–729

    PubMed  CAS  Google Scholar 

  146. Mise M, Arii S, Higashituji H, Furutani M, Niwano M, Harada T, Ishigami S et al (1996) Clinical significance of vascular endothelial growth factor and basic fibroblast growth factor gene expression in liver tumor. Hepatology 23:455–464

    Article  PubMed  CAS  Google Scholar 

  147. Nakashima Y, Nakashima O, Hsia CC, Kojiro M, Tabor E (1999) Vascularization of small hepatocellular carcinomas: correlation with differentiation. Liver 19:12–18

    Article  PubMed  CAS  Google Scholar 

  148. Miura H, Miyazaki T, Kuroda M, Oka T, Machinami R, Kodama T, Shibuya M et al (1997) Increased expression of vascular endothelial growth factor in human hepatocellular carcinoma. J Hepatol 27:854–861

    Article  PubMed  CAS  Google Scholar 

  149. Chow NH, Hsu PI, Lin XZ, Yang HB, Chan SH, Cheng KS, Huang SM et al (1997) Expression of vascular endothelial growth factor in normal liver and hepatocellular carcinoma: an immunohistochemical study. Hum Pathol 28: 698–703

    Article  PubMed  CAS  Google Scholar 

  150. Chao Y, Li CP, Chau GY, Chen CP, King KL, Lui WY, Yen SH et al (2003) Prognostic significance of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin in patients with resectable hepatocellular carcinoma after surgery. Ann Surg Oncol 10:355–362

    Article  PubMed  Google Scholar 

  151. Zhou XD (2002) Recurrence and metastasis of hepatocellular carcinoma: progress and prospects. Hepatobiliary Pancreat Dis Int 1:35–41

    PubMed  Google Scholar 

  152. Marzullo A, Vacca A, Roncali L, Pollice L, Ribatti D (1998) Angiogenesis in hepatocellular carcinoma: an experimental study in the chick embryo chorioallantoic membrane. Int J Oncol 13:17–21

    PubMed  CAS  Google Scholar 

  153. Poon RT-P, Lau CP-Y, Cheung S-T, Yu W-C, Fan S-T (2003) Quantitative correlation of serum levels and tumor expression of vascular endothelial growth factor in patients with hepatocellular carcinoma. Cancer Res 63:3121–3126

    PubMed  CAS  Google Scholar 

  154. Jinno K, Tanimizu M, Hyodo I, Nishikawa Y, Hosokawa Y, Doi T, Endo H et al (1998) Circulating vascular endothelial growth factor (VEGF) is a possible tumor marker for metastasis in human hepatocellular carcinoma. J Gastroenterol 33:376–382

    Article  PubMed  CAS  Google Scholar 

  155. Poon RT, Ng IO, Lau C, Zhu LX, Yu WC, Lo CM, Fan ST et al (2001) Serum vascular endothelial growth factor predicts venous invasion in hepatocellular carcinoma: a prospective study. Ann Surg 233:227–235

    Article  PubMed  CAS  Google Scholar 

  156. Kim SJ, Choi IK, Park KH, Yoon SY, Oh SC, Seo JH, Choi CW et al (2004) Serum vascular endothelial growth factor per platelet count in hepatocellular carcinoma: correlations with clinical parameters and survival. Jpn J Clin Oncol 34:184–190

    Article  PubMed  Google Scholar 

  157. Poon R, Lau C, Yu W, Fan S, Wong J (2004) High serum levels of vascular endothelial growth factor predict poor response to transarterial chemoembolization in hepatocellular carcinoma: a prospective study. Oncol Rep 11: 1077–1084

    PubMed  CAS  Google Scholar 

  158. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390

    Article  PubMed  CAS  Google Scholar 

  159. Llovet JM, Bruix J (2008) Molecular targeted therapies in hepatocellular carcinoma. Hepatology 48:1312–1327

    Article  PubMed  CAS  Google Scholar 

  160. Liao X, Yi J, Li X, Yang Z, Deng W, Tian G (2003) Expression of angiogenic factors in hepatocellular carcinoma after transcatheter arterial chemoembolization. J Huazhong Univ Sci Technolog Med Sci 23:280–282

    Article  PubMed  Google Scholar 

  161. Suzuki H, Mori M, Kawaguchi C, Adachi M, Miura S, Ishii H (1999) Serum vascular endothelial growth factor in the course of transcatheter arterial embolization of hepatocellular carcinoma. Int J Oncol 14:1087–1090

    PubMed  CAS  Google Scholar 

  162. Li X, Feng G, Zheng C, Zhuo C, Liu X (2003) Influence of transarterial chemoembolization on angiogenesis and expression of vascular endothelial growth factor and basic fibroblast growth factor in rat with Walker-256 transplanted hepatoma: An experimental study. World J Gastroenterol 9:2445–2449

    PubMed  CAS  Google Scholar 

  163. Wu H, Feng G, Liang H, Zheng C, Li X (2004) Vascular endothelial growth factor antisense oligodeoxynucleotides with lipiodol in arterial embolization of liver cancer in rats. World J Gastroenterol 10:813–818

    PubMed  CAS  Google Scholar 

  164. Strebel BM, Dufour JF (2008) Combined approach to hepatocellular carcinoma: a new treatment concept for nonresectable disease. Expert Rev Anticancer Ther 8:1743–1749

    Article  PubMed  CAS  Google Scholar 

  165. Kraft A, Weindel K, Ochs A, Marth C, Zmija J, Schumacher P, Unger C et al (1999) Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer 85:178–187

    Article  PubMed  CAS  Google Scholar 

  166. Zebrowski BK, Liu W, Ramirez K, Akagi Y, Mills GB, Ellis LM (1999) Markedly elevated levels of vascular endothelial growth factor in malignant ascites. Ann Surg Oncol 6:373–378

    Article  PubMed  CAS  Google Scholar 

  167. Verheul HMW, Hoekman K, Jorna AS, Smit EF, Pinedo HM (2000) Targeting vascular endothelial growth factor blockade: ascites and pleural effusion formation. Oncologist 5:45–50

    Article  PubMed  CAS  Google Scholar 

  168. Dong W, Sun X, Yu B, Luo H, Yu J (2003) Role of VEGF and CD44v6 in differentiating benign from malignant ascites. World J Gastroenterol 9:2596–2600

    PubMed  CAS  Google Scholar 

  169. Roberts WG, Palade GE (1995) Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 108(pt 6): 2369–2379

    PubMed  CAS  Google Scholar 

  170. Roberts WG, Palade GE (1997) Neovasculature induced by vascular endothelial growth factor is fenestrated. Cancer Res 57:765–772

    PubMed  CAS  Google Scholar 

  171. Hirata A, Baluk P, Fujiwara T, McDonald DM (1995) Location of focal silver staining at endothelial gaps in inflamed venules examined by scanning electron microscopy. Am J Physiol 269:L403–L418

    Google Scholar 

  172. Neal CR, Michel CC (1995) Transcellular gaps in microvascular walls of frog and rat when permeability is increased by perfusion with the ionophore A23187. J Physiol 488(Pt 2):427–437

    PubMed  CAS  Google Scholar 

  173. Kohn S, Nagy JA, Dvorak HF, Dvorak AM (1992) Pathways of macromolecular tracer transport across venules and small veins. Structural basis for the hyperpermeability of tumor blood vessels. Lab Invest 67:596–607

    PubMed  CAS  Google Scholar 

  174. Feng D, Nagy J, Dvorak A, Dvorak H (2000) Different pathways of macromolecule extravasation from hyperpermeable tumor vessels. Microvasc Res 59:24–37

    Article  PubMed  CAS  Google Scholar 

  175. Grunstein J, Roberts WG, Mathieu-Costello O, Hanahan D, Johnson RS (1999) Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. Cancer Res 59:1592–1598

    PubMed  CAS  Google Scholar 

  176. Funyu J, Mochida S, Inao M, Matsui A, Fujiwara K (2001) VEGF can act as vascular permeability factor in the hepatic sinusoids through upregulation of porosity of endothelial cells. Biochem Biophys Res Commun 280:481–485

    Article  PubMed  CAS  Google Scholar 

  177. Yoshiji H, Kuriyama S, Hicklin D, Huber J, Yoshii J, Ikenaka Y, Noguchi R et al (2001) The vascular endothelial growth factor receptor KDR/Flk-1 is a major regulator of malignant ascites formation in the mouse hepatocellular carcinoma model. Hepatology 33:841–847

    Article  PubMed  CAS  Google Scholar 

  178. Stoelcker B, Echtenacher B, Weich H, Sztajer H, Hicklin D, Mannel D (2000) VEGF/Flk-1 interaction, a requirement for malignant ascites recurrence. J Interferon Cytokine Res 20:511–517

    Article  PubMed  CAS  Google Scholar 

  179. Shibuya M, Luo J, Toyoda M, Yamaguchi S (1999) Involvement of VEGF and its receptors in ascites tumor formation. Cancer Chemother Pharmacol 43 Suppl:S72–S77

    Google Scholar 

  180. Mesiano S, Ferrara N, Jaffe RB (1998) Role of vascular endothelial growth factor in ovarian cancer: inhibition of ascites formation by immunoneutralization. Am J Pathol 153:1249–1256

    PubMed  CAS  Google Scholar 

  181. Byrne AT, Ross L, Holash J, Nakanishi M, Hu L, Hofmann JI, Yancopoulos GD et al (2003) Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res 9:5721–5728

    PubMed  CAS  Google Scholar 

  182. Xu L, Yoneda J, Herrera C, Wood J, Killion J, Fidler I (2000) Inhibition of malignant ascites and growth of human ovarian carcinoma by oral administration of a potent inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. Int J Oncol 16:445–454

    PubMed  CAS  Google Scholar 

  183. Melgar-Lesmes P, Tugues S, Ros J, Fernandez-Varo G, Morales-Ruiz M, Rodes J, Jimenez W (2009) Vascular endothelial growth factor and angiopoietin-2 play a major role in the pathogenesis of vascular leakage in cirrhotic rats. Gut 58:285–292

    Article  PubMed  CAS  Google Scholar 

  184. Perez-Ruiz M, Ros J, Morales-Ruiz M, Navasa M, Colmenero J, Ruiz-del-Arbol L, Cejudo P et al (1999) Vascular endothelial growth factor production in peritoneal macrophages of cirrhotic patients: regulation by cytokines and bacterial lipopolysaccharide. Hepatology 29: 1057–1063

    Article  PubMed  CAS  Google Scholar 

  185. Arai S, Mochida S, Ohno A, Ishikawa K, Matsui A, Arai M, Shibuya M et al (1999) Decreased expression of receptors for vascular endothelial growth factor and sinusoidal endothelial cell damage in cold-preserved rat livers. Transplant Proc 31:2668–2672

    Article  PubMed  CAS  Google Scholar 

  186. Boros P, Tarcsafalvi A, Wang L, Megyesi J, Liu J, Miller CM (2001) Intrahepatic expression and release of vascular endothelial growth factor following orthotopic liver transplantation in the rat. Transplantation 72:805–811

    Article  PubMed  CAS  Google Scholar 

  187. Mitchell A, Adams LA, MacQuillan G, Tibballs J, Vanden Driesen R, Delriviere L (2008) Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia. Liver Transpl 14:210–213

    Article  PubMed  Google Scholar 

  188. Cho ML, Cho CS, Min SY, Kim SH, Lee SS, Kim WU, Min DJ et al (2002) Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts. Arthritis Rheum 46:1202–1209

    Article  PubMed  CAS  Google Scholar 

  189. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ et al (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8:128–135

    Article  PubMed  CAS  Google Scholar 

  190. Luan FL, Ding R, Sharma VK, Chon WJ, Lagman M, Suthanthiran M (2003) Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int 63: 917–926

    Article  PubMed  CAS  Google Scholar 

  191. Shibuya M, Claesson-Welsh L (2006) Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 312:549–560

    Article  PubMed  CAS  Google Scholar 

  192. Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8: 579–591

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute of Clinical Pharmacology and Visceral Research, University of Bern, Murtenstrasse 35, 3010, Bern, Switzerland

    David Semela & Jean-François Dufour

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  1. David Semela
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  2. Jean-François Dufour
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Correspondence to Jean-François Dufour .

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Editors and Affiliations

  1. Inselspital, Universität Bern, Murtenstr. 35, Bern, 3010, Switzerland

    Jean-Francois Dufour

  2. Klinik für Viszeral- und, Universitätsspital Zürich, Rämistr. 100, Zürich, 8091, Switzerland

    Pierre-Alain Clavien

Selected Reading

Selected Reading

1. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676 (this review provides a detailed and comprehensive description of the different VEGF isoforms and receptors and discusses their role under physiological and pathological conditions [20])

2. Shibuya M, Claesson-Welsh L (2006) Signal transduction by VEGF receptors in regulation of angiogenesis and ­lymphangiogenesis. Exp Cell Res 312:549–560 (this review ­outlines the current knowledge about the signal transduction properties of the different VEGF receptors [191])

3.Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of antitumor activity. Nat Rev Cancer 8:579–591 (this article reviews the recent advances and mechanisms of VEGF-targeted therapies in tumors [192])

4. LeCouter J, Moritz DR, Li B et al (2003) Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 299:890–893 (describes the paracrine cross talk between hepatocytes and liver sinusoidal endothelial cells during hepatocyte growth [64])

5. http://www.nature.com/focus/angiogenesis/ (this joint web focus on angiogenesis with a special section on VEGF signaling is a project between the journals Nature Medicine and Nature Reviews Cancer. The web site provides review articles and a selection of “classic” papers nominated by experts in the field of angiogenesis)

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Semela, D., Dufour, JF. (2010). VEGF Signaling. In: Dufour, JF., Clavien, PA. (eds) Signaling Pathways in Liver Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00150-5_28

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