Download PDF
Semin Thromb Hemost 2000; 26(5): 553-560
DOI: 10.1055/s-2000-13212
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Functions of the VEGF/VEGF Receptor System in the Vascular System

Georg Breier
  • Department of Molecular Biology, Max-Planck-Institut für physiologische und klinische Forschung, Bad Nauheim, Germany
Further Information

Publication History

Publication Date:
31 December 2000 (online)

    Permissions and Reprints

ABSTRACT

The vascular endothelial growth factor (VEGF)/VEGF receptor system plays a central regulatory role in physiological and pathological angiogenesis. During embryogenesis, the VEGF/VEGF receptor system is critically involved in the formation of the vascular system by regulating both the growth and the survival of blood vessels. In the vasculature of the adult organism, the high-affinity signaling VEGF receptor-2 (VEGFR-2) is downregulated but is reinduced during transient phases of physiological angiogenesis. Moreover, a variety of pathological conditions are associated with the upregulation of VEGF and the VEGF receptors. VEGF stimulates angiogenesis and the survival of endothelial cells in tumors, thereby enabling tumor expansion and metastasis. VEGF is also upregulated in ischemic diseases, such as coronary heart disease or stroke, and is thought to stimulate the-often insufficient-compensatory formation of blood vessels. The implication of VEGF in these pathological processes has opened up promising new therapeutic strategies. In malignancies, attempts are made to inhibit VEGF-mediated signaling and angiogenesis. In ischemic disease, the exogenous application of VEGF may enhance the formation of collaterals. However, considering the complexity of the regulatory pathways involved in the formation of new blood vessels under physiological conditions, a treatment relying on VEGF as the sole angiogenic factor may be insufficient, and the combination with other factors may improve the functionality of newly formed blood vessels and the efficacy of therapeutic angiogenesis.

KEYWORD

Vascular endothelial growth factor (VEGF) - VEGF receptor - angiogenesis - tumor - ischemic disorders

REFERENCES

  • 1 Risau W, Flamme I. Vasculogenesis.  Annu Rev Cell Dev Biol . 1995;  11 73-91
    CrossrefPubMedGoogle Scholar
  • 2 Risau W. Mechanisms of angiogenesis.  Nature . 1997;  386 671-674
    CrossrefPubMedGoogle Scholar
  • 3 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease.  Nature Med . 1995;  1 27-31
    CrossrefPubMedGoogle Scholar
  • 4 O'Reilly M S, Boehm T, Shing Y. Endostatin: An endogenous inhibitor of angiogenesis and tumor growth.  Cell . 1997;  88 277-285
    CrossrefPubMedGoogle Scholar
  • 5 Boehm T, Folkman J, Browder T, O'Reilly M S. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance.  Nature . 1997;  390 404-407
    CrossrefPubMedGoogle Scholar
  • 6 Plate K H. Control of tumor growth via inhibition of tumor angiogenesis.  Adv Exp Med Biol . 1998;  451 57-61
    PubMedGoogle Scholar
  • 7 Ferrara N. Vascular endothelial growth factor: molecular and biological aspects.  Curr Top Microbiol Immunol . 1999;  237 1-30
    PubMedGoogle Scholar
  • 8 Marti H H, Risau W. Angiogenesis in ischemic disease.  Thromb Haemost . 1999;  82(Suppl 1) 44-52
    PubMedGoogle Scholar
  • 9 Schaper W, Buschmann I. Arteriogenesis, the good and bad of it.  Eur Heart J . 1999;  20 1297-1299
    CrossrefPubMedGoogle Scholar
  • 10 Carmeliet P. Mechanisms of angiogenesis and arteriogenesis.  Nature Med . 2000;  6 389-395
    CrossrefPubMedGoogle Scholar
  • 11 Strömblad S, Cheresh D A. Cell adhesion and angiogenesis.  Trends Cell Biol . 1996;  6 462-468
    CrossrefPubMedGoogle Scholar
  • 12 Breviario F, Caveda L, Corada M. Functional properties of human vascular endothelial cadherin (7B4/cadherin-5), an endothelium-specific cadherin.  Arterioscler Thromb Vasc Biol . 1995;  15 1229-1239
    PubMedGoogle Scholar
  • 13 Carmeliet P, Ferreira V, Breier G. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.  Nature . 1996;  380 435-439
    CrossrefPubMedGoogle Scholar
  • 14 Ferrara N, Carver-Moore K, Chen H. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene.  Nature . 1996;  380 439-442
    CrossrefPubMedGoogle Scholar
  • 15 Flamme I, von Reutern M, Drexler H CA, Syedali S, Risau W. Overexpression of vascular endothelial growth factor in the avian embryo induces hypervascularization and increased vascular permeability without alterations of embryonic pattern formation.  Dev Biol . 1995;  171 399-414
    CrossrefPubMedGoogle Scholar
  • 16 Drake C J, Little C D. Exogenous vascular endothelial growth factor induces malformed and hyperfused vessels during embryonic neovascularization.  Proc Natl Acad Sci USA . 1995;  92 7657-7661
    PubMedGoogle Scholar
  • 17 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.  Nature Med . 1999;  5 495-502
    PubMedGoogle Scholar
  • 18 Shalaby F, Rossant J, Yamaguchi T P. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice.  Nature . 1995;  376 62-66
    CrossrefPubMedGoogle Scholar
  • 19 Alon T, Hemo I, Itin A. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity.  Nature Med . 1995;  1 1024-1028
    CrossrefPubMedGoogle Scholar
  • 20 Fong G H, Zhang L, Bryce D M, Peng J. Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice.  Development . 1999;  126 3015-3025
    PubMedGoogle Scholar
  • 21 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
  • 22 Clark D E, Smith S K, He Y. A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation.  Biol Reprod . 1998;  59 1540-1548
    CrossrefPubMedGoogle Scholar
  • 23 Kawasaki T, Kitsukawa T, Bekku Y. A requirement for neuropilin-1 in embryonic vessel formation.  Development . 1999;  126 4895-4902
    PubMedGoogle Scholar
  • 24 Kitsukawa T, Shimizu M, Sanbo M. Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice.  Neuron . 1997;  19 995-1005
    CrossrefPubMedGoogle Scholar
  • 25 Gerber H P, Hillan K J, Ryan A M. VEGF is required for growth and survival in neonatal mice.  Development . 1999;  126 1149-1159
    PubMedGoogle Scholar
  • 26 Gerber H P, Vu T H, Ryan A M. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation.  Nature Med . 1999;  5 623-628
    PubMedGoogle Scholar
  • 27 Ferrara N, Chen H, Davis-Smyth T. Vascular endothelial growth factor is essential for corpus luteum angiogenesis.  Nature Med . 1998;  4 336-340
    PubMedGoogle Scholar
  • 28 Persico M G, Vincenti V, DiPalma T. Structure, expression and receptor-binding properties of placenta growth factor (PlGF).  Curr Top Microbiol Immunol . 1999;  237 31-40
    PubMedGoogle Scholar
  • 29 Khaliq A, Li X F, Shams M. Localisation of placenta growth factor (PIGF) in human term placenta.  Growth Factors . 1996;  13 243-250
    PubMedGoogle Scholar
  • 30 Athanassiades A, Lala P K. Role of placenta growth factor (PIGF) in human extravillous trophoblast proliferation, migration and invasiveness.  Placenta . 1998;  19 465-473
    CrossrefPubMedGoogle Scholar
  • 31 Breier G, Clauss M, Risau W. Coordinate expression of vascular endothelial growth factor receptor-1 (flt-1) and its ligand suggests a paracrine regulation of murine vascular development.  Dev Dyn . 1995;  204 228-239
    PubMedGoogle Scholar
  • 32 Park J E, Chen H H, Winer J, 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
  • 33 Carmeliet P, Collen D. Role of vascular endothelial growth factor and vascular endothelial growth factor receptors in vascular development.  Curr Top Microbiol Immunol . 1999;  237 133-158
    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 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 Sci USA . 1998;  95 11709-11714
    CrossrefPubMedGoogle Scholar
  • 36 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
  • 37 Jeltsch M, Kaipainen A, Joukov V. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice.  Science . 1997;  276 1423-1425
    CrossrefPubMedGoogle Scholar
  • 38 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
  • 39 Dumont D J, Jussila L, Taipale J. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3.  Science . 1998;  282 946-949
    CrossrefPubMedGoogle Scholar
  • 40 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
  • 41 Plate K H, Breier G, Weich H A, Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo.  Nature . 1992;  359 845-848
    CrossrefPubMedGoogle Scholar
  • 42 Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.  Nature . 1992;  359 843-845
    CrossrefPubMedGoogle Scholar
  • 43 Damert A, Machein M, Breier G. Up-regulation of vascular endothelial growth factor expression in a rat glioma is conferred by two distinct hypoxia-driven mechanisms.  Cancer Res . 1997;  57 3860-3864
    PubMedGoogle Scholar
  • 44 Kremer C, Breier G, Risau W, Plate K H. Up-regulation of flk-1/vascular endothelial growth factor receptor 2 by its ligand in a cerebral slice culture system.  Cancer Res . 1997;  57 3852-3859
    PubMedGoogle Scholar
  • 45 Shen B Q, Lee D Y, Gerber H P. Homologous up-regulation of KDR/Flk-1 receptor expression by vascular endothelial growth factor in vitro.  J Biol Chem . 1998;  273 29979-29985
    CrossrefPubMedGoogle Scholar
  • 46 Waltenberger J, Mayr U, Pentz S, Hombach V. Functional upregulation of the vascular endothelial growth factor receptor KDR by hypoxia.  Circulation . 1996;  94 1647-1654
    PubMedGoogle Scholar
  • 47 Patterson C, Wu Y, Lee M E. Nuclear protein interactions with the human KDR/flk-1 promoter in vivo. Regulation of Sp1 binding is associated with cell type-specific expression.  J Biol Chem . 1997;  272 8410-8416
    CrossrefPubMedGoogle Scholar
  • 48 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
  • 49 Kappel A, Schlaeger T M, Flamme I. Role of SCL/Tal-1, GATA and Ets transcription factor binding sites for the regulation of Flk-1 during murine vascular development.  Blood. 2000;  96 (in press)
    PubMedGoogle Scholar
  • 50 Vandenbunder B, Pardanaud L, Jaffredo T, Mirabel M A, Stehelin D. Complementary patterns of expression of c-ets 1, c-myb and c-myc in the blood-forming system of the chick embryo.  Development . 1989;  107 265-274
    PubMedGoogle Scholar
  • 51 Wernert N, Raes M B, Lassalle P. c-ets1 Proto-oncogene is a transcription factor expressed in endothelial cells during tumor vascularization and other forms of angiogenesis in humans.  Am J Pathol . 1992;  140 119-127
    PubMedGoogle Scholar
  • 52 Millauer B, Wizigmann-Voos S, Schnürch H. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis.  Cell . 1993;  72 835-846
    CrossrefPubMedGoogle Scholar
  • 53 Plate K H, Breier G, Millauer B, Ullrich A, Risau W. Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis.  Cancer Res . 1993;  53 5822-5827
    PubMedGoogle Scholar
  • 54 Kim K J, Li B, Winer J. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo.  Nature . 1993;  362 841-844
    CrossrefPubMedGoogle Scholar
  • 55 Millauer B, Shawver L K, Plate K H, Risau W, Ullrich A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant.  Nature . 1994;  367 576-579
    CrossrefPubMedGoogle Scholar
  • 56 Millauer B, Longhi M P, Plate K H. Dominant-negative inhibition of Flk-1 suppresses the growth of many tumor types in vivo.  Cancer Res . 1996;  56 1615-1620
    PubMedGoogle Scholar
  • 57 Machein M R, Risau W, Plate K H. Antiangiogenic gene therapy in a rat glioma model using a dominant-negative vascular endothelial growth factor receptor 2.  Hum Gene Ther . 1999;  10 1117-1128
    CrossrefPubMedGoogle Scholar
  • 58 Eberhard A, Kahlert S, Goede V. Heterogeneity of angiogenesis and blood vessel maturation in human tumors: Implications for antiangiogenic tumor therapies.  Cancer Res . 2000;  60 1388-1393
    PubMedGoogle Scholar
  • 59 Benjamin L E, Keshet E. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: Induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal.  Proc Natl Acad Sci USA . 1997;  94 8761-8766
    CrossrefPubMedGoogle Scholar
  • 60 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
  • 61 Fong T A, 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
  • 62 Ferrara N, Alitalo K. Clinical applications of angiogenic growth factors and their inhibitors.  Nature Med . 1999;  5 1359-1364
    CrossrefPubMedGoogle Scholar
  • 63 Breier G, Albrecht U, Sterrer S, Risau W. Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation.  Development . 1992;  114 521-532
    PubMedGoogle Scholar
  • 64 Roberts W G, Palade G E. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor.  J Cell Sci . 1995;  108 2369-2379
    PubMedGoogle Scholar
  • 65 Esse S, Wolburg K, Wolburg H. Vascular endothelial growth factor induces endothelial fenestrations in vitro.  J Cell Biol . 1998;  140 947-959
    CrossrefPubMedGoogle Scholar
  • 66 Asahara T, Chen D, Tsurumi Y. Accelerated restitution of endothelial integrity and endothelium-dependent function after phVEGF165 gene transfer.  Circulation . 1996;  94 3291-3302
    PubMedGoogle Scholar
  • 67 Takeshita S, Pu L Q, Stein L A. Intramuscular administration of vascular endothelial growth factor induces dose-dependent collateral artery augmentation in a rabbit model of chronic limb ischemia.  Circulation . 1994;  90 228-234
    PubMedGoogle Scholar
  • 68 Takeshita S, Zheng L P, Brogi E. Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model.  J Clin Invest . 1994;  93 662-670
    CrossrefPubMedGoogle Scholar
  • 69 Bauters C, Asahara T, Zheng L P. Site-specific therapeutic angiogenesis after systemic administration of vascular endothelial growth factor.  J Vasc Surg . 1995;  21 314-324
    PubMedGoogle Scholar
  • 70 Takeshita S, Tsurumi Y, Couffinahl T. Gene transfer of naked DNA encoding for three isoforms of vascular endothelial growth factor stimulates collateral development in vivo.  Lab Invest . 1996;  75 487-501
    PubMedGoogle Scholar
  • 71 Harada K, Friedman M, Lopez J J. Vascular endothelial growth factor administration in chronic myocardial ischemia.  Am J Physiol . 1996;  270 H1791-H1802
    PubMedGoogle Scholar
  • 72 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
  • 73 Losordo D W, Vale P R, Symes J F. Gene therapy for myocardial angiogenesis: Initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia.  Circulation . 1998;  98 2800-2804
    PubMedGoogle Scholar
  • 74 Baumgartner I, Pieczek A, Manor O. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia.  Circulation . 1998;  97 1114-1123
    CrossrefPubMedGoogle Scholar
  • 75 Rosengart T K, Lee L Y, Patel S R. Angiogenesis gene therapy: Phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease.  Circulation . 1999;  100 468-474
    PubMedGoogle Scholar
  • 76 Henry T D. Therapeutic angiogenesis.  Br Med J . 1999;  318 1536-1539
    PubMedGoogle Scholar
  • 77 Thurston G, McLean J W, Rizen M. Cationic liposomes target angiogenic endothelial cells in tumors and chronic inflammation in mice.  J Clin Invest . 1998;  101 1401-1413
    PubMedGoogle Scholar
  • 78 Asahara T, Bauters C, Zheng L P. Synergistic effect of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in vivo.  Circulation . 1995;  92 II365-II371
    PubMedGoogle Scholar
  • 79 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
  • 80 Gale N W, Yancopoulos G D. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development.  Genes Dev . 1999;  13 1055-1066
    PubMedGoogle Scholar