The biology of VEGF and its receptors


Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions. The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2, which differ considerably in signaling properties. Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies. VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration.

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Figure 1: The VEGF isoforms and their interaction with VEGF receptors.

Debbie Maizels

Figure 2: Role of the VEGF receptor tyrosine kinases in different cell types.

Debbie Maizels

Figure 3: Differential effects of VEGFR-1 (R1) and VEGFR-2 (R2) in LSECs.

Debbie Maizels


  1. 1

    Folkman, J. & Shing, Y. Angiogenesis. J. Biol. Chem. 267, 10931–10934 (1992).

  2. 2

    Yancopoulos, G.D. et al. Vascular-specific growth factors and blood vessel formation. Nature 407, 242–248 (2000).

  3. 3

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

  4. 4

    Ferrara, N. & Alitalo, K. Clinical applications of angiogenic growth factors and their inhibitors. Nat. Med. 5, 1359–1364 (1999).

  5. 5

    Carmeliet, P. Mechanisms of angiogenesis and arteriogenesis. Nat. Med. 6, 389–395 (2000).

  6. 6

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

  7. 7

    Neufeld, G., Cohen, T., Gengrinovitch, S. & Poltorak, Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 13, 9–22 (1999).

  8. 8

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

  9. 9

    Leung, D.W., Cachianes, G., Kuang, W.J., Goeddel, D.V. & Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306–1309 (1989).

  10. 10

    Plouet, J., Schilling, J. & Gospodarowicz, D. Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT20 cells. EMBO J. 8, 3801–3808 (1989).

  11. 11

    Nagy, J.A. et al. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J. Exp. Med. 196, 1497–1506 (2002).

  12. 12

    Matsumoto, T. & Claesson-Welsh, L. VEGF receptor signal transduction. Science STKE 112 (RE21), 1–17 (2001).

  13. 13

    Compernolle, V. et al. Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat. Med. 8, 702–710 (2002).

  14. 14

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

  15. 15

    Gerber, H.P. et al. VEGF regulates endothelial cell survival by the PI3-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J. Biol. Chem. 273, 30366–30343 (1998).

  16. 16

    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. 103, 159–165 (1999).

  17. 17

    Yuan, F. et al. 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. USA 93, 14765–14770 (1996).

  18. 18

    Gerber, H.P. et al. VEGF is required for growth and survival in neonatal mice. Development 126, 1149–1159 (1999).

  19. 19

    Clauss, M. et al. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J. Exp. Med. 172, 1535–1545 (1990).

  20. 20

    Broxmeyer, H.E. et al. Myeloid progenitor cell regulatory effects of vascular endothelial cell growth factor. Int. J. Hematol. 62, 203–215 (1995).

  21. 21

    Gabrilovich, D.I. et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med. 2, 1096–1103 (1996).

  22. 22

    Hattori, K. et al. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J. Exp Med. 193, 1005–1014 (2001).

  23. 23

    Gerber, H.-P. et al. Vascular endothelial growth factor regulates hematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417, 954–958 (2002).

  24. 24

    Senger, D.R. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983–985 (1983).

  25. 25

    Dvorak, H.F., Brown, L.F., Detmar, M. & Dvorak, A.M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am. J. Pathol. 146, 1029–1039 (1995).

  26. 26

    Bates, D.O. & Curry, F.E. Vascular endothelial growth factor increases microvascular permeability via a Ca(2+)-dependent pathway. Am. J. Physiol. 273, H687–H694 (1997).

  27. 27

    Roberts, W.G. & Palade, G.E. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J. Cell Sci. 108, 2369–2379 (1995).

  28. 28

    Ku, D.D., Zaleski, J.K., Liu, S. & Brock, T.A. Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries. Am. J. Physiol. 265, H586–H592 (1993).

  29. 29

    Yang, R. et al. Effects of vascular endothelial growth factor on hemodynamics and cardiac performance. J. Cardiovasc. Pharmacol. 27, 838–844 (1996).

  30. 30

    Houck, K.A. et al. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol. Endocrinol. 5, 1806–1814 (1991).

  31. 31

    Tischer, E. et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J. Biol. Chem. 266, 11947–11954 (1991).

  32. 32

    Ferrara, N. & Henzel, W.J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun. 161, 851–858 (1989).

  33. 33

    Houck, K.A., Leung, D.W., Rowland, A.M., Winer, J. & Ferrara, N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J. Biol. Chem. 267, 26031–26037 (1992).

  34. 34

    Park, J.E., Keller, H.-A. & Ferrara, N. The vascular endothelial growth factor isoforms (VEGF): differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol. Biol. Cell 4, 1317–1326 (1993).

  35. 35

    Keyt, B.A. et al. The carboxyl-terminal domain (111–165) of vascular endothelial growth factor is critical for its mitogenic potency. J. Biol. Chem. 271, 7788–7795 (1996).

  36. 36

    Carmeliet, P. et al. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelila growth factor isoforms VEGF164 and VEGF188 . Nat. Med. 5, 495–502 (1999).

  37. 37

    Ruhrberg, C. et al. Spatially restricted patterning cues provided by heparin-binding VEGFA control blood vessel branching morphogenesis. Genes Dev. 16, 2684–2698 (2002).

  38. 38

    Dor, Y., Porat, R. & Keshet, E. Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis. Am. J. Physiol. 280, C1367–C1374 (2001).

  39. 39

    Semenza, G. Signal transduction to hypoxia-inducible factor 1. Biochem. Pharmacol. 64, 993–998 (2002).

  40. 40

    Mole, D.R., Maxwell, P.H., Pugh, C.W. & Ratcliffe, P.J. Regulation of HIF by the von Hippel-Lindau tumour suppressor: implications for cellular oxygen sensing. IUBMB Life 52, 43–47 (2001).

  41. 41

    Siemeister, G. et al. Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. Cancer Res. 56, 2299–2301 (1996).

  42. 42

    Iliopoulos, O., Levy, A.P., Jiang, C., Kaelin, W.G. & Goldberg, M.A. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc. Natl. Acad. Sci. USA 93, 10595–10599 (1996).

  43. 43

    Maxwell, P.H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).

  44. 44

    Maxwell, P.H. & Ratcliffe, P.J. Oxygen sensors and angiogenesis. Semin. Cell Dev. Biol. 13, 29–37 (2002).

  45. 45

    Safran, M. & Kaelin, W.J. HIF hydroxylation and the mammalian oxygen-sensing pathway. J. Clin Invest. 111, 779–783 (2003).

  46. 46

    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. 270, 25915–25919 (1995).

  47. 47

    Okada, F. et al. 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 95, 3609–3614 (1998).

  48. 48

    Shibuya, M. et al. Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase (flt) closely related to the fms family. Oncogene 8, 519–527 (1990).

  49. 49

    Terman, B.I. et al. Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 6, 1677–1683 (1991).

  50. 50

    de Vries, C. et al. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255, 989–991 (1992).

  51. 51

    Gerber, H.P., Condorelli, F., Park, J. & Ferrara, N. Differential transcriptional regulation of the two VEGF receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J. Biol. Chem. 272, 23659–23667 (1997).

  52. 52

    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. 269, 25646–25654 (1994).

  53. 53

    Olofsson, B. et al. Vascular endothelial growth factor B (VEGFB) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc. Natl. Acad. Sci. USA 95, 11709–11714 (1998).

  54. 54

    Kendall, R.L. & Thomas, K.A. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc. Natl. Acad. Sci. USA 90, 10705–10709 (1993).

  55. 55

    Davis-Smyth, T., Chen, H., Park, J., Presta, L.G. & Ferrara, N. The second immunoglobulin-like domain of the VEGF tyrosine kinase receptor Flt-1 determines ligand binding and may initiate a signal transduction cascade. EMBO J. 15, 4919–4927 (1996).

  56. 56

    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. 269, 26988–26995 (1994).

  57. 57

    Carmeliet, P. et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat. Med. 7, 575–583 (2001).

  58. 58

    Gille, H. et al. A repressor sequence in the juxtamembrane domain of Flt-1 (VEGFR-1) constitutively inhibits VEGF-dependent PI 3 kinase activation and endothelial cell migration. EMBO J. 19, 4064–4073 (2000).

  59. 59

    Maru, Y., Yamaguchi, S. & Shibuya, M. Flt-1, a receptor for vascular endothelial growth factor, has transforming and morphogenic potentials. Oncogene 16, 2585–2595 (1998).

  60. 60

    Fong, G.H., Rossant, J., Gertsenstein, M. & Breitman, M.L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66–70 (1995).

  61. 61

    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 126, 3015–3025 (1999).

  62. 62

    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 4, 9349–9354 (1998).

  63. 63

    Barleon, B. et al. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87, 3336–3343 (1996).

  64. 64

    Hiratsuka, S. et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2, 289–300 (2002).

  65. 65

    Hattori, K. et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat. Med. 8, 841–849 (2002).

  66. 66

    Luttun, A. et al. Revascularization of ischemic tissues by PLGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat. Med. 8, 831–840 (2002).

  67. 67

    LeCouter, J. et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 299, 890–893 (2003).

  68. 68

    Terman, B.I. et al. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem. Biophys. Res. Commun. 187, 1579–1586 (1992).

  69. 69

    Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995).

  70. 70

    Guo, D., Jia, Q., Song, H.Y., Warren, R.S. & Donner, D.B. 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 (1995).

  71. 71

    Eliceiri, B.P. et al. Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol. Cell 4, 915–924 (1999).

  72. 72

    Takahashi, T., Ueno, H. & Shibuya, M. VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene 18, 2221–2230 (1999).

  73. 73

    Gille, H. et al. Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific VEGF mutants. J. Biol. Chem. 276, 3222–3230 (2001).

  74. 74

    Adini, A., Kornaga, T., Firoozbakht, F. & Benjamin, L.E. Placental growth factor is a survival factor for tumor endothelial cells and macrophages. Cancer Res. 62, 2749–2752 (2002).

  75. 75

    Soker, S., Fidder, H., Neufeld, G. & Klagsbrun, M. Characterization of novel vascular endothelial growth factor (VEGF) receptors on tumor cells that bind VEGF165 via its exon 7-encoded domain. J. Biol. Chem. 271, 5761–5767 (1996).

  76. 76

    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 92, 735–745 (1998).

  77. 77

    Neufeld, G. et al. The neuropilins: multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovasc. Med. 12, 13–19 (2002).

  78. 78

    Kawasaki, T. et al. A requirement for neuropilin-1 in embryonic vessel formation, Development 126, 4895–4902 (1999).

  79. 79

    Lee, P. et al. Neuropilin-1 is required for vascular development and is a mediator of VEGF-dependent angiogenesis in zebrafish. Proc. Natl. Acad. Sci. USA 99, 10470–10475 (2002).

  80. 80

    Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996).

  81. 81

    Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439–442 (1996).

  82. 82

    Bellomo, D. et al. Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ. Res. 86, E29–E35 (2000).

  83. 83

    Kitamoto, Y., Tokunaga, H. & Tomita, K. Vascular endothelial growth factor is an essential molecule for mouse kidney development: glomerulogenesis and nephrogenesis. J. Clin. Invest. 99, 2351–2357 (1997).

  84. 84

    Eremina, V. et al. Glomerular-specific alterations of VEGFA expression lead to distinct congenital and acquired renal diseases. J. Clin. Invest. 111, 707–716 (2003).

  85. 85

    Ryan, A.M. et al. Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal antibody. Toxicol. Pathol. 27, 78–86 (1999).

  86. 86

    Poole, A.R. The growth plate: cellular physiology, cartilage assembly and mineralization. in Cartilage: Molecular Aspects (eds. Hall, B.K. & Newman, S.A.) 179–211 (CRC Press, Boca Raton, Florida, 1991).

  87. 87

    Gerber, H.P. et al. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat. Med. 5, 623–628 (1999).

  88. 88

    Haigh, J.J., Gerber, H.P., Ferrara, N. & Wagner, E.F. Conditional inactivation of VEGFA in areas of collagen2a1 expression results in embryonic lethality in the heterozygous state. Development 127, 1445–1453 (2000).

  89. 89

    Zelzer, E. et al. Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development 129, 1893–1904 (2002).

  90. 90

    Goede, V., Schmidt, T., Kimmina, S., Kozian, D. & Augustin, H.G. Analysis of blood vessel maturation processes during cyclic ovarian angiogenesis. Lab. Invest. 78, 1385–1394 (1998).

  91. 91

    Phillips, H.S., Hains, J., Leung, D.W. & Ferrara, N. Vascular endothelial growth factor is expressed in rat corpus luteum. Endocrinology 127, 965–967 (1990).

  92. 92

    Ferrara, N. et al. Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat. Med. 4, 336–340 (1998).

  93. 93

    Fraser, H.M. et al. Suppression of luteal angiogenesis in the primate after neutralization of vascular endothelial growth factor. Endocrinology 141, 995–1000 (2000).

  94. 94

    Zimmermann, R.C. et al. Short-term administration of antivascular endothelial growth factor antibody in the late follicular phase delays follicular development in the rhesus monkey. J. Clin. Endocrinol. Metab. 86, 768–772 (2001).

  95. 95

    LeCouter, J. et al. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature 412, 877–884 (2001).

  96. 96

    LeCouter, J., Lin, R. & Ferrara, N. Endocrine gland-derived VEGF and the emerging hypothesis of organ-specific regulation of angiogenesis. Nat. Med. 8, 913–917 (2002).

  97. 97

    Ferrara, N. et al. Differential expression of the angiogenic factor genes VEGF and EG-VEGF in normal and polycystic human ovaries. Am. J. Path. 162, 1881–1893 (2003).

  98. 98

    Kim, K.J. et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 362, 841–844 (1993).

  99. 99

    Fukumura, D. et al. Tumor induction of VEGF promoter activity in stromal cells. Cell 94, 715–725 (1998).

  100. 100

    Gerber, H.P., Kowalski, J., Sherman, D., Eberhard, D.A. & Ferrara, N. Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res. 60, 6253–6258 (2000).

  101. 101

    Tsuzuki, Y. et al. Vascular endothelial growth factor (VEGF) modulation by targeting hypoxia-inducible factor-1α—> hypoxia response element—> VEGF cascade differ entially regulates vascular response and growth rate in tumors, Cancer Res. 60, 6248–6252 (2000).

  102. 102

    Inoue, M., Hager, J.H., Ferrara, N., Gerber, H.P. & Hanahan, D. VEGFA has a critical, nonredundant role in angiogenic switching and pancreatic β cell carcinogenesis. Cancer Cell. 1, 193–202 (2002).

  103. 103

    Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2, 737–744 (2000).

  104. 104

    Klement, G. et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest. 105, R15–R24 (2000).

  105. 105

    Lee, C.G. et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res. 60, 5565–5570 (2000).

  106. 106

    Presta, L.G. et al. Humanization of an anti-VEGF monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 57, 4593–4599 (1997).

  107. 107

    Prewett, M. et al. Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis. Cancer Res. 59, 5209–5218 (1999).

  108. 108

    Wood, J.M. et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 60, 2178–2189 (2000).

  109. 109

    Holash, J. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc. Natl. Acad. Sci. USA 99, 11393–11398 (2002).

  110. 110

    Kabbinavar, F. et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J. Clin. Oncol. 21, 60–65 (2003).

  111. 111

    Yang, J.C. et al. A randomized trial of bevacizumab (anti-VEGF antibody) in metastatic renal cancer. N. Engl. J. Med. (in the press).

  112. 112

    Gerber, H.P. & Ferrara, N. The role of VEGF in normal and neoplastic hematopoiesis. J. Mol. Med. 81, 20–31 (2003).

  113. 113

    Smolich, B.D. et al. The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemi blasts. Blood 97, 1413–1421 (2001).

  114. 114

    Dias, S. et al. Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J. Clin. Invest. 106, 511–521 (2000).

  115. 115

    Garner, A. Vascular diseases. in Pathobiology of Ocular Disease 2nd edn. (eds. Garner, A. & Klintworth, G.K.) 1625–1710 (Marcel Dekker, New York, 1994).

  116. 116

    Aiello, L.P. et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N. Engl. J. Med. 331, 1480–1487 (1994).

  117. 117

    Malecaze, F. et al. Detection of vascular endothelial growth factor mRNA and vascular endothelial growth factor-like activity in proliferative diabetic retinopathy. Arch. Ophthalmol. 112, 1476–1482 (1994).

  118. 118

    Aiello, L.P. et al. 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 92, 10457–10461 (1995).

  119. 119

    Adamis, A.P. et al. Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch. Ophthalmol. 114, 66–71 (1996).

  120. 120

    Lopez, P.F., Sippy, B.D., Lambert, H.M., Thach, A.B. & Hinton, D.R. Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest. Ophthalmol. Vis. Sci. 37, 855–868 (1996).

  121. 121

    Chen, Y. et al. Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured Fab in complex with antigen. J. Mol. Biol. 293, 865–881 (1999).

  122. 122

    Ruckman, J. et al. 2'-Fluoropyrimidine RNA-based aptamers to the 165-amino acid form of vascular endothelial growth factor (VEGF165). Inhibition of receptor binding and VEGF-induced vascular permeability through interactions requiring the exon 7-encoded domain. J. Biol. Chem. 273, 20556–20567 (1998).

  123. 123

    Krzystolik, M.G. et al. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch. Ophthalmol. 120, 338–346 (2002).

  124. 124

    Detmar, M. et al. Keratinocyte-derived vascular permeability factor (vascular endothelial growth factor) is a potent mitogen for dermal microvascular endothelial cells. J. Invest. Dermatol. 105, 44–50 (1995).

  125. 125

    Detmar, M. et al. Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice. J. Invest. Dermatol. 111, 1–6 (1998).

  126. 126

    Cramer, T. HIF1α is essential for myeloid cell-mediated inflammation. Cell 112, 645–657 (2003).

  127. 127

    Kovacs, Z., Ikezaki, K., Samoto, K., Inamura, T. & Fukui, M. VEGF and flt. Expression time kinetics in rat brain infarct. Stroke 27, 1865–1872 (1996).

  128. 128

    van Bruggen, N. et al. VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J. Clin. Invest. 104, 1613–1620 (1999).

  129. 129

    Paul, R. et al. Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke. Nat. Med. 7, 222–227 (2001).

  130. 130

    Yen, S.S.C. Polycystic ovary syndrome (hyperandrogenic chronic anovulation). in Reproductive Endocrinology (eds. Yen, S.S.C., Jaffe, R.B. & Barbieri, R.L.) 436–478 (W.B. Saunders, Philadelphia, 1999).

  131. 131

    McLaren, J. et al. Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. J. Clin. Invest. 98, 482–489 (1996).

  132. 132

    Maynard, S.E. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Invest. 111, 649–658 (2003).

  133. 133

    Kerbel, R. & Folkman, J. Clinical translation of angiogenesis inhibitors. Nat. Rev. Cancer 2, 727–739 (2002).

  134. 134

    Henry, T.D. et al. The VIVA trial: Vascular endothelial growth factor in ischemia for vascular angiogenesis. Circulation 107, 1359–1365 (2003).

  135. 135

    Makinen, K. et al. Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomized, placebo-controlled, double-blinded phase II study. Mol. Ther. 6, 127–133 (2002).

  136. 136

    Dor, Y. et al. Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J. 21, 1939–1947 (2002).

  137. 137

    Street, J. et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc. Natl. Acad. Sci. USA 99, 9656–9661 (2002).

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Correspondence to Napoleone Ferrara.

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

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