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Semin Thromb Hemost 2000; 26(5): 561-570
DOI: 10.1055/s-2000-13213
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Molecular Biology of the VEGF and the VEGF Receptor Family

Matthias Clauss
  • MPI für Physiologische und Klinische Forschung, Bad Nauheim, Germany
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Publication History

Publication Date:
31 December 2000 (online)

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ABSTRACT

Vascular endothelial growth factor (VEGF) is the founding member of a still growing family of endothelial cell growth factors. The diverse functions of VEGF and its homologues (PlGF, VEGF-B, VEGF-C, VEGF-D, and VEGF-E) can be explained by their differential binding to the three signaling VEGF receptors. The VEGF family members PlGF and VEGF-B with exclusive binding capacities to the VEGFR-1 can influence monocyte activation and differentiation. The VEGFR-2 and VEGFR-3 binding VEGF homologues, VEGF-C and VEGF-D, are mitogens for both vascular and lymphatic endothelial cells. The orf virus encoded VEGF-E homologue binds and activates only the VEGFR-2 and thus may be the prototype of a vascular endothelial cell-specific growth factor. Further specific activities of VEGF and its homologues result from receptor-specific signaling and differential expression of ligands or receptors. A naturally occurring soluble form of the VEGFR-1 suggests a regulatory role for this receptor. Finally, the production and activation of factors involved in the coagulation/fibrinolytic system provide further evidence for the hypothesis that processes of hemostasis are involved in angiogenesis.

KEYWORD

VEGF - homologues - VEGF receptors - signaling - angiogenesis - hemostasis

REFERENCES

  • 1 Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors.  FASEB J . 1999;  13 9-22
    PubMedGoogle Scholar
  • 2 Kukk E, Lymboussaki A, Taira S. VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development.  J Biol Chem . 1996;  271 1270-1273
    CrossrefPubMedGoogle Scholar
  • 3 Jeltsch M, Kaipainen A, Joukov V. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice.  Science . 1997;  276 1423-1425
    CrossrefPubMedGoogle Scholar
  • 4 Muller Y A, Christinger H W, Keyt B A, de Vos M A. The crystal structure of vascular endothelial growth factor (VEGF) refined to 1.93 A resolution: Multiple copy flexibility and receptor binding.  Structure . 1997;  5 1325-1338
    CrossrefPubMedGoogle Scholar
  • 5 Wiesmann C, Fuh G, Christinger H W. Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor.  Cell . 1997;  91 695-704
    CrossrefPubMedGoogle Scholar
  • 6 Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice.  Proc Natl Acad Sci USA . 1998;  95 9349-9354
    CrossrefPubMedGoogle Scholar
  • 7 Soker S, Takashima S, Miao H Q, Neufeld G, Klagsbrun M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor.  Cell . 1998;  92 735-745
    CrossrefPubMedGoogle Scholar
  • 8 Miao H Q, Soker S, Feiner L. Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell motility: Functional competition of collapsin-1 and vascular endothelial growth factor-165.  J Cell Biol . 1999;  146 233-241
    PubMedGoogle Scholar
  • 9 Dougher M, Terman B I. Autophosphorylation of KDR in the kinase domain is required for maximal VEGF-stimulated kinase activity and receptor internalization.  Oncogene . 1999;  18 1619-1627
    CrossrefPubMedGoogle Scholar
  • 10 Fong T AT, Shawver L K, Sun L. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types.  Cancer Res . 1999;  59 99-106
    PubMedGoogle Scholar
  • 11 D'Angelo G, Martini J F, Iiri T. 16K human prolactin inhibits vascular endothelial growth factor-induced activation of Ras in capillary endothelial cells.  Mol Endocrinol . 1999;  13 692-704
    CrossrefPubMedGoogle Scholar
  • 12 Gerber H P, McMurtrey A, Kowalski J. 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 . 1998;  273 30336-30343
    CrossrefPubMedGoogle Scholar
  • 13 Takahashi T, Shibuya M. The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-gamma pathway and partially induces mitotic signals in NIH3T3 fibroblasts.  Oncogene . 1997;  14 2079-2089
    CrossrefPubMedGoogle Scholar
  • 14 Wu H M, Yuan Y, Zawieja D C, Tinsley J, Granger H J. Role of phospholipase C, protein kinase C, and calcium in VEGF-induced venular hyperpermeability.  Am J Physiol . 1999;  276 H535-H542.
    PubMedGoogle Scholar
  • 15 Fischer S, Clauss M, Wiesnet M. Hypoxia induces permeability in brain microvessel endothelial cells via VEGF and NO.  Am J Physiol . 1999;  276 C812-C820
    PubMedGoogle Scholar
  • 16 Murohara T, Horowitz J R, Silver M. Vascular endothelial growth factor/vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin.  Circulation . 1998;  97 99-107
    CrossrefPubMedGoogle Scholar
  • 17 Mayhan W G. VEGF increases permeability of the blood-brain barrier via a nitric oxide synthase/cGMP-dependent pathway.  Am J Physiol . 1999;  276 C1148-C1153
    PubMedGoogle Scholar
  • 18 Shen B Q, Lee D Y, Zioncheck T F. Vascular endothelial growth factor governs endothelial nitric-oxide synthase expression via a KDR/Flk-1 receptor and a protein kinase C signaling pathway.  J Biol Chem . 1999;  274 33057-33063
    CrossrefPubMedGoogle Scholar
  • 19 Parenti A, Morbidelli L, Cui X L. Nitric oxide is an upstream signal of vascular endothelial growth factor-induced extracellular signal-regulated kinase1/2 activation in postcapillary endothelium.  J Biol Chem . 1998;  273 4220-4226
    CrossrefPubMedGoogle Scholar
  • 20 Goligorsky M S, Abedi H, Noiri E. Nitric oxide modulation of focal adhesions in endothelial cells.  Am J Physiol . 1999;  276 C1271-C1281
    PubMedGoogle Scholar
  • 21 Papapetropoulos A, Garcia-Cardena G, Madri J A, Sessa W C. Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells.  J Clin Invest . 1999;  100 3131-3139
    PubMedGoogle Scholar
  • 22 Ziche M, Morbidelli L, Choudhuri R. Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis.  J Clin Invest . 1997;  99 2625-2634
    PubMedGoogle Scholar
  • 23 Morbidelli L, Chang C H, Douglas J G. Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium.  Am J Physiol . 1996;  270 H411-H415
    PubMedGoogle Scholar
  • 24 Rousseau S, Houle F, Landry J, Huot J. p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells.  Oncogene . 1997;  15 2169-2177
    CrossrefPubMedGoogle Scholar
  • 25 Marumo T, Schini-Kerth V B, Busse R. Vascular endothelial growth factor activates nuclear factor-kappa B and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells.  Diabetes . 1999;  48 1131-1137
    PubMedGoogle Scholar
  • 26 Haas E, Grell M, Wajant H, Scheurich P. Continuous autotropic signaling by membrane-expressed tumor necrosis factor.  J Biol Chem . 1999;  274 18107-18112
    CrossrefPubMedGoogle Scholar
  • 27 Mechtcheriakova D, Wlachos A, Holzmüller H, Binder B R, Hofer E. Vascular endothelial cell growth factor-induced tissue factor expression in endothelial cells is mediated by EGR-1.  Blood . 1999;  93 3811-3823
    PubMedGoogle Scholar
  • 28 Bierhaus A, Zhang Y, Deng Y. Mechanism of the tumour-necrosis factor-α-mediated induction of endothelial tissue factor.  J Biol Chem . 1995;  270 26419-26432
    CrossrefPubMedGoogle Scholar
  • 29 Moll T, Czyz M, Holzmüller H. Regulation of the tissue factor promoter in endothelial cells. Binding of NF kappa B-, AP-1-, and Sp1-like transcription factors.  J Biol Chem . 1995;  270 3849-3857
    CrossrefPubMedGoogle Scholar
  • 30 Banks R E, Forbes M A, Searles J. Evidence for the existence of a novel pregnancy-associated soluble variant of the vascular endothelial growth factor receptor, Flt-1.  Mol Hum Reprod . 1998;  4 377-386
    CrossrefPubMedGoogle Scholar
  • 31 Shen H, Clauss M, Ryan J. Characterization of vascular-permeability factor/vascular endothelial growth-factor receptors on mononuclear phagocytes.  Blood . 1993;  81 2767-2773
    PubMedGoogle Scholar
  • 32 Desai J, Holt-Shore V, Torry R J, Caudle M R, Torry D S. Signal transduction and biological function of placenta growth factor in primary human trophoblast.  Biol Reprod . 1999;  60 887-892
    PubMedGoogle Scholar
  • 33 Hauser S, Weich H. A heparin-binding form of placenta growth factor (PlGF-2) is expressed in human umbilical vein endothelial cells and in placenta.  Growth Factors . 1993;  9 259-268
    PubMedGoogle Scholar
  • 34 Olofsson B, Pajusola K, Kaipainen A. Vascular endothelial growth factor B, a novel growth factor for endothelial cells.  Proc Natl Acad Sci USA . 1996;  93 2576-2581
    CrossrefPubMedGoogle Scholar
  • 35 Joukov V, Pajusola K, Kaipainen A. 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 . 1996;  15 290-298
    PubMedGoogle Scholar
  • 36 Achen M G, Jeltsch M, Kukk E. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4).  Proc Natl Acad Sci USA . 1998;  95 548-553
    CrossrefPubMedGoogle Scholar
  • 37 Meyer M, Clauss M, Lepple-Wienhues A. A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases.  EMBO J . 1999;  18 363-374
    CrossrefPubMedGoogle Scholar
  • 38 Ogawa S, Oku A, Sawano A. A novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain.  J Biol Chem . 1998;  273 31273-31282
    CrossrefPubMedGoogle Scholar
  • 39 Andersson M, Ostman A, Backstrom G. Assignment of interchain disulfide bonds in platelet-derived growth-factor (PDGF) and evidence for agonist activity of monomeric PDGF.  J Biol Chem . 1992;  267 11260-11266
    PubMedGoogle Scholar
  • 40 Fuh G, Li B, Crowley C, Cunningham B, Wells J A. Requirements for binding and signaling of the kinase domain receptor for vascular endothelial growth factor.  J Biol Chem . 1998;  273 11197-11204
    CrossrefPubMedGoogle Scholar
  • 41 Keyt B A, Nguyen H V, Berleau L T. Identification of vascular endothelial growth factor determinants for binding KDR and FLT-1 receptors. Generation of receptor-selective VEGF variants by site-directed mutagenesis.  J Biol Chem . 1996;  271 5638-5646
    CrossrefPubMedGoogle Scholar
  • 42 Carmeliet P, Ng Y S, Nuyens D. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188.  Nat Med . 1999;  5 495-502
    PubMedGoogle Scholar
  • 43 Park J E, Chen H H, Winer H, Houck K A, Ferrara N. 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 . 1994;  269 25646-25654
    PubMedGoogle Scholar
  • 44 Ziche M, Maglione D, Ribatti D. Placenta growth factor-1 is chemotactic, mitogenic, and angiogenic.  Lab Invest . 1997;  76 517-531
    PubMedGoogle Scholar
  • 45 Cao Y, Chen H, Zhou L. Heterodimers of placenta growth factor/vascular endothelial growth factor.  J Biol Chem . 1995;  271 3154-3162
    PubMedGoogle Scholar
  • 46 Clauss M, Weich H, Breier G. The vascular endothelial growth factor receptor flt-1 mediates biological activities: Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis.  J Biol Chem . 1996;  271 17629-17634
    PubMedGoogle Scholar
  • 47 Sawano A, Takahashi T, Yamaguchi S, Aonuma M, Shibuya M. Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor.  Cell Growth Differ . 1996;  7 213-221
    PubMedGoogle Scholar
  • 48 Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin C-H. Different signal transduction properties of KDR and flt1, two receptors for vascular endothelial growth factor.  J Biol Chem . 1994;  269 26988-26995
    PubMedGoogle Scholar
  • 49 Landgren E, Schiller P, Cao Y, Claesson-Welsh L. Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-gamma and migration of endothelial cells expressing Flt 1.  Oncogene . 1998;  16 359-367
    CrossrefPubMedGoogle Scholar
  • 50 Olofsson B, Korpelainen E, Pepper M S. Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells.  Proc Natl Acad Sciences USA . 1998;  95 11709-11714
    CrossrefPubMedGoogle Scholar
  • 51 Cao Y, Linden P, Farnebo J. Vascular endothelial growth factor C induces angiogenesis in vivo.  Proc Natl Acad Sci USA . 1998;  95 14389-14394
    CrossrefPubMedGoogle Scholar
  • 52 Witzenbichler B, Asahara T, Murohara T. Vascular endothelial growth factor-C (VEGF-C/VEGF-2) promotes angiogenesis in the setting of tissue ischemia.  Am J Pathol . 1998;  153 381-394
    PubMedGoogle Scholar
  • 53 Dumont D J, Jussila L, Taipale J. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3.  Science . 1998;  282 946-949
    CrossrefPubMedGoogle Scholar
  • 54 Ohta Y, Shridhar V, Bright R K. VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours.  Br J Cancer . 1999;  81 54-61
    CrossrefPubMedGoogle Scholar
  • 55 Yonemura Y, Endo Y, Fujita H. Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer.  Clin Cancer Res . 1999;  5 1823-1829
    PubMedGoogle Scholar
  • 56 Joukov V, Kumar V, Sorsa T. A recombinant mutant vascular endothelial growth factor-C that has lost vascular endothelial growth factor receptor-2 binding, activation, and vascular permeability activities.  J Biol Chem . 1998;  273 6599-6602
    CrossrefPubMedGoogle Scholar
  • 57 Hewett P W, Murray J C. Coexpression of flt-1, flt-4 and KDR in freshly isolated and cultured human endothelial cells.  Biochem Biophys Res Commun . 1996;  221 697-702
    CrossrefPubMedGoogle Scholar
  • 58 Pepper M S, Mandriota S J, Jeltsch M, Kumar V, Alitalo K. Vascular endothelial growth factor (VEGF)-C synergizes with basic fibroblast growth factor and VEGF in the induction of angiogenesis in vitro and alters endothelial cell extracellular proteolytic activity.  J Cell Physiol . 1998;  177 439-452
    CrossrefPubMedGoogle Scholar
  • 59 Marconcini L, Marchio S, Morbidelli L. c-fos-induced growth factor/vascular endothelial growth factor D induces angiogenesis in vivo and in vitro.  Proc Natl Acad Sci USA . 1999;  96 9671-9676
    CrossrefPubMedGoogle Scholar
  • 60 Wise L M, Veikkola T, Mercer A A. Vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1.  Proc Natl Acad Sci USA . 1999;  96 3071-3076
    CrossrefPubMedGoogle Scholar
  • 61 Haig D, McInnes C, Deane D. Cytokines and their inhibitors in orf virus infection.  Vet Immunol Immunopathol . 1996;  54 261-267
    PubMedGoogle Scholar
  • 62 Clauss M, Gerlach M, Gerlach H. Vascular permeability factor: A tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration.  J Exp Med . 1990;  172 1535-1545
    CrossrefPubMedGoogle Scholar
  • 63 Gabrilovich D I, Chen H L, Girgis K R. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dentritic cells.  Nat Med . 1996;  2 1096-1103
    CrossrefPubMedGoogle Scholar
  • 64 Barleon B, Sozanni S, Zhou D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1.  Blood . 1996;  87 3336-3343
    PubMedGoogle Scholar
  • 65 Guerrin M, Moukadiri H, Chollet P. Vasculotropin vascular endothelial growth-factor is an autocrine growth-factor for human retinal-pigment epithelial-cells cultured in vitro.  J Cell Physiol . 1995;  164 385-394
    CrossrefPubMedGoogle Scholar
  • 66 Silverman W F, Krum J M, Mani N, Rosenstein J M. Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures.  Neuroscience . 1999;  90 1529-1541
    CrossrefPubMedGoogle Scholar
  • 67 Clauss M. Functions of the VEGF receptor-1 (flt-1) in the vasculature.  Trends Cardiovasc Med . 1998;  8 241-245
    CrossrefPubMedGoogle Scholar
  • 68 Watanabe Y, Dvorak H F. Vascular permeability factor/vascular endothelial growth factor inhibits anchorage-disruption-induced apoptosis in microvessel endothelial cells by inducing scaffold formation.  Exp Cell Res . 1997;  233 340-349
    CrossrefPubMedGoogle Scholar
  • 69 Benjamin L E, Golijanin D, Itin A, Pode D, Keshet E. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal.  J Clin Invest . 1999;  103 159-165
    CrossrefPubMedGoogle Scholar
  • 70 Fernandez Pujol B, Lucibello F C, Gehling U M. Endothelial-like cells derived from human CD14 positive monocytes.  Differentiation . 2000;  65 287-300
    CrossrefPubMedGoogle Scholar
  • 71 Senger D, Galli S, Dvorak A. Vascular permeability factor.  Science . 1983;  219 983-986
    CrossrefPubMedGoogle Scholar
  • 72 Keck P J, Hauser S D, Krivi G. Vascular permeability factor, an endothelial cell mitogen related to PDGF.  Science . 1989;  246 1309-1312
    PubMedGoogle Scholar
  • 73 Nawroth P P, Handley D, Matsueda G. Tumor necrosis factor/cachetin-induced intravascular fibrin formation in meth A fibrosarcoma.  J Exp Med . 1988;  168 637-645
    CrossrefPubMedGoogle Scholar
  • 74 Carroll V A, Binder B R. The role of the plasminogen activation system in cancer .  Semin Thromb Hemost . 1999;  25 183-197
    Article in Thieme ConnectPubMedGoogle Scholar
  • 75 Wartiovaara U, Salven P, Mikkola H. Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation.  Thromb Haemost . 1998;  80 171-175
    PubMedGoogle Scholar
  • 76 Wang H S, Li F, Runge M S, Chaikof E L. Endothelial cells exhibit differential chemokinetic and mitogenic responsiveness to alpha-thrombin.  J Surg Res . 1997;  68 139-144
    CrossrefPubMedGoogle Scholar
  • 77 Nehls V, Herrmann R. The configuration of fibrin clots determines capillary morphogenesis and endothelial cell migration.  Microvasc Res . 1996;  51 347-364
    PubMedGoogle Scholar
  • 78 Zucker S, Mirza H, Conner C E. 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.  Internat J Cancer . 1998;  75 780-786
    CrossrefPubMedGoogle Scholar
  • 79 Keyt B A, Berleau L T, Nguyen H V. The carboxyl-terminal domain (111-165) of vascular endothelial growth factor is critical for its mitogenic potency.  J Biol Chem . 1996;  271 7788-7795
    CrossrefPubMedGoogle Scholar
  • 80 Semenza G L. Perspectives on oxygen sensing.  Cell . 1999;  98 281-284
    CrossrefPubMedGoogle Scholar
  • 81 Dor Y, Keshet E. Ischemia-driven angiogenesis.  Trends Cardiovasc Med . 1997;  7 289-294
    CrossrefPubMedGoogle Scholar
  • 82 Ikeda E, Achen M G, Breier G, Risau W. Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells.  J Biol Chem . 1995;  270 19761-19766
    CrossrefPubMedGoogle Scholar
  • 83 Kotch L E, Iyer N V, Laughner E, Semenza G L. Defective vascularization of HIF-1 alpha-null embryos is not associated with VEGF deficiency but with mesenchymal cell death.  Dev Biol . 1999;  209 254-267
    CrossrefPubMedGoogle Scholar
  • 84 Ema M, Taya S, Yokotani N. A novel BHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1-alpha regulates the VEGF expression and is potentially involved in lung and vascular development.  Proc Natl Acad Sci USA . 1997;  94 4273-4278
    CrossrefPubMedGoogle Scholar
  • 85 Kappel A, Ronicke V, Damert A. Identification of vascular endothelial growth factor (VEGF) receptor-2 (Flk-1) promoter enhancer sequences sufficient for angioblast and endothelial cell-specific transcription in transgenic mice.  Blood . 1999;  93 4284-4292
    PubMedGoogle Scholar
  • 86 Ristimaki A, Narko K, Enholm B, Joukov V, Alitalo K. Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C.  J Biol Chem . 1998;  273 8413-8418
    CrossrefPubMedGoogle Scholar
  • 87 Enholm B, Paavonen K, Ristimaki A. Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia.  Oncogene . 1997;  14 2475-2483
    CrossrefPubMedGoogle Scholar
  • 88 Stein I, Neeman M, Shweiki D, Itin A, Keshet E. Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes.  Mol Cell Biol . 1995;  15 5363-5368
    PubMedGoogle Scholar
  • 89 Adamis A P, Shima D T, Yeo K T. Synthesis and secretion of vascular permeability factor vascular endothelial growth factor by human retinal pigment epithelial cells.  Biochem Biophys Res Commun . 1993;  193 631-638
    CrossrefPubMedGoogle Scholar
  • 90 Aiello L P, Pierce E A, Foley E D, Takagi H, Chen H. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins.  Proc Natl Acad Sci USA . 1995;  92 10457-10461
    CrossrefPubMedGoogle Scholar
  • 91 Pal S, Claffey K P, Dvorak H F, Mukhopadhyay D. The von Hippel-Lindau gene product inhibits vascular permeability factor vascular endothelial growth factor expression in renal cell carcinoma by blocking protein kinase pathways.  J Biol Chem. . 1997;  272 27509-27512
    CrossrefPubMedGoogle Scholar
  • 92 Mukhopadhyay D, Knebelmann B, Cohen H T, Ananth S, Sukhatme V P. The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity.  Mol Cell Biol . 1997;  17 5629-5639
    PubMedGoogle Scholar
  • 93 Machein M R, Kullmer J, Ronicke V. Differential downregulation of vascular endothelial growth factor by dexamethasone in normoxic and hypoxic rat glioma cells.  Neuropathol Appl Neurobiol . 1999;  25 104-112
    CrossrefPubMedGoogle Scholar
  • 94 Stavri G T, Hong Y, Zachary I C. Hypoxia and platelet-derived growth factor synergistically upregulate the expression of vascular endothelial growth factor in vascular smooth muscle cells.  FEBS Lett . 1995;  358 311-315
    CrossrefPubMedGoogle Scholar
  • 95 Finkenzeller G, Sparacio A, Technau A, Marme D, Siemeister G. Sp1 recognition sites in the proximal promoter of the human vascular endothelial growth factor gene are essential for platelet-derived growth factor-induced gene expression.  Oncogene . 1997;  15 669-676
    CrossrefPubMedGoogle Scholar
  • 96 Gille J, Swerlick R A, Caughman S W. Transforming growth factor-alpha-induced transcriptional activation of the vascular permeability factor (VPF/VEGF) gene requires AP-2-dependent DNA binding and transactivation.  EMBO J . 1997;  16 750-759
    CrossrefPubMedGoogle Scholar
  • 97 Silins G, Grimmond S, Egerton M, Hayward N. Analysis of the promoter region of the human VEGF-related factor gene.  Biochem Biophys Res Commun . 1997;  230 413-418
    CrossrefPubMedGoogle Scholar
  • 98 Chin L, Tam A, Pomerantz J. Essential role for oncogenic Ras in tumour maintenance.  Nature . 1999;  400 468-472
    CrossrefPubMedGoogle Scholar
  • 99 Okada F, Rak J W, Stcroix B. Impact of oncogenes in tumor angiogenesis-mutant K-Ras up-regulation of vascular endothelial growth factor vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells.  Proc Natl Acad Sci USA . 1998;  95 3609-3614
    CrossrefPubMedGoogle Scholar
  • 100 Grugel S, Finkenzeller G, Weindel K, Barleon B, Marme D. Both v-Ha-ras and v-raf stimulate expression of the vascular endothelial growth factor in NIH 3T3 cells.  J Biol Chem . 1995;  270 25915-25919
    CrossrefPubMedGoogle Scholar
  • 101 Rak J, Mitsuhashi Y, Bayko L. Mutant Ras oncogenes upregulate VEGF/VPF expression: Implications for induction and inhibition of tumor angiogenesis.  Cancer Res . 1995;  55 4575-4580
    PubMedGoogle Scholar
  • 102 Ellis L M, Staley C A, Liu W B. Down-regulation of vascular endothelial growth factor in a human colon carcinoma cell line transfected with an antisense expression vector specific for c-src J Biol Chem .  1998;  273 1052-1057
    PubMedGoogle Scholar
  • 103 Zhang Y, Deng Y, Luther T. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice.  J Clin Invest . 1994;  94 1320-1327
    Google Scholar
  • 104 Ollivier V, Bentolila S, Chabbat J, Hakim J, Deprost D. Tissue factor-dependent vascular endothelial growth factor production by human fibroblasts in response to activated factor VII.  Blood . 1998;  91 2698-2703
    PubMedGoogle Scholar
  • 105 Ruf W, Mueller B M. Tissue factor signaling.  Thromb Haemost . 1999;  82 175-182
    PubMedGoogle Scholar
  • 106 Ott I, Fischer E G, Miyagi Y, Mueller B M, Ruf W. A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280.  J Cell Biol . 1998;  140 1241-1253
    Google Scholar