Molecular Diversity

, 10:515 | Cite as

Molecular and functional diversity of vascular endothelial growth factors

Review

Summary

Members of the vascular endothelial growth factor (VEGF) family are crucial regulators of neovascularization and are classified as cystine knot growth factors that specifically bind cellular receptor tyrosine kinases VEGFR-1, VEGFR-2, and VEGFR-3 with high but variable affinity and selectivity. The VEGF family has recently been expanded and currently comprises seven members: VEGF-A, VEGF-B, placenta growth factor (PlGF), VEGF-C, VEGF-D, viral VEGF (also known as VEGF-E), and snake venom VEGF (also known as VEGF-F). Although all members are structurally homologous, there is molecular diversity among the subtypes, and several isoforms, such as VEGF-A, VEGF-B, and PlGF, are generated by alternative exon splicing. These splicing isoforms exhibit differing properties, particularly in binding to co-receptor neuropilins and heparin. VEGF family proteins play multiple physiological roles, such as angiogenesis and lymphangiogenesis, while exogenous members (viral and snake venom VEGFs) display activities that are unique in physiology and function. This review will highlight the molecular and functional diversity of VEGF family proteins.

Keywords

angiogenesis biological property endothelial cell proliferation lymphangiogenesis molecular diversity receptor selectivity receptor binding affinity vascular endothelial growth factor vascular permeability 

Abbreviations:

HF

hypotensive factor

HIF

hypoxia-inducible factor

ICPP

increasing capillary permeability protein

NP

neuropilin

PlGF

placenta growth factor

RTK

receptor tyrosine kinase

svVEGF

snake venom vascular endothelial growth factor

VEGF

vascular endothelial growth factor

VEGFR

VEGF receptor

References

  1. 1.
    Risau, W. and Flamme, I., Vasculogenesis, Annu. Rev. Cell Dev. Biol., 11 (1995) 73–91.Google Scholar
  2. 2.
    Asahara, T., Murohara, T., Sullivan, A., Silver, M., van der Zee, R., Li, T., Witzenbichler, B., Schatteman, G. and Isner, J.M., Isolation of putative progenitor endothelial cells for angiogenesis, Science, 275 (1997) 964–967.Google Scholar
  3. 3.
    He, Y., Rajantie, I., Ilmonen, M., Makinen, T., Karkkainen, M.J., Haiko, P., Salven, P. and Alitalo, K., Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis, Cancer Res., 64 (2004) 3737–3740.Google Scholar
  4. 4.
    Gothert, J.R., Gustin, S.E., van Eekelen, J.A., Schmidt, U., Hall, M.A., Jane, S.M., Green, A.R., Gottgens, B., Izon, D.J. and Begley, C.G., Genetically tagging endothelial cells in vivo: Bone marrow-derived cells do not contribute to tumor endothelium, Blood, 104 (2004) 1769–1777.Google Scholar
  5. 5.
    Risau, W., Mechanisms of angiogenesis, Nature, 386 (1997) 671–674.Google Scholar
  6. 6.
    Folkman, J., Angiogenesis in cancer, vascular, rheumatoid and other disease, Nat. Med., 1 (1995) 27–31.Google Scholar
  7. 7.
    Nisato, R.E., Tille, J.C. and Pepper, M.S., Lymphangiogenesis and tumor metastasis, Thromb Haemost, 90 (2003) 591–597.Google Scholar
  8. 8.
    Stacker, S.A., Williams, R.A. and Achen, M.G., Lymphangiogenic growth factors as markers of tumor metastasis, APMIS, 112 (2004) 539–549.Google Scholar
  9. 9.
    Achen, M.G., McColl, B.K. and Stacker, S.A., Focus on lymphangiogenesis in tumor metastasis, Cancer Cell, 7 (2005) 121–127.Google Scholar
  10. 10.
    Tammela, T., Petrova, T.V. and Alitalo, K., Molecular lymphangiogenesis: New players, Trends Cell Biol., 15 (2005) 434–441.Google Scholar
  11. 11.
    Ferrara, N., Vascular endothelial growth factor: Basic science and clinical progress, Endocr Rev., 25 (2004) 581–611.Google Scholar
  12. 12.
    McColl, B.K., Stacker, S.A. and Achen, M.G., Molecular regulation of the VEGF family – inducers of angiogenesis and lymphangiogenesis, APMIS, 112 (2004) 463–480.Google Scholar
  13. 13.
    Tammela, T., Enholm, B., Alitalo, K. and Paavonen, K., The biology of vascular endothelial growth factors, Cardiovasc Res., 65 (2005) 550–563.Google Scholar
  14. 14.
    Takahashi, H. and Shibuya, M., The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions, Clin. Sci. (Lond), 109 (2005) 227–241.CrossRefGoogle Scholar
  15. 15.
    Cross, M.J., Dixelius, J., Matsumoto, T. and Claesson-Welsh, L., VEGF-receptor signal transduction, Trends Biochem. Sci., 28 (2003) 488–494.Google Scholar
  16. 16.
    Neufeld, G., Cohen, T., Gengrinovitch, S. and Poltorak, Z., Vascular endothelial growth factor (VEGF) and its receptors, FASEB J., 13 (1999) 9–22.Google Scholar
  17. 17.
    Yancopoulos, G.D., Davis, S., Gale, N.W., Rudge, J.S., Wiegand, S.J. and Holash, J., Vascular-specific growth factors and blood vessel formation, Nature, 407 (2000) 242–248.Google Scholar
  18. 18.
    Carmeliet, P., Angiogenesis in health and disease, Nat. Med., 9 (2003) 653–660.Google Scholar
  19. 19.
    Jain, R.K., Molecular regulation of vessel maturation, Nat. Med., 9 (2003) 685–693.Google Scholar
  20. 20.
    Lohela, M., Saaristo, A., Veikkola, T. and Alitalo, K., Lymphangiogenic growth factors, receptors and therapies, Thromb Haemost, 90 (2003) 167–184.Google Scholar
  21. 21.
    Yamane, A., Seetharam, L., Yamaguchi, S., Gotoh, N., Takahashi, T., Neufeld, G. and Shibuya, M., 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 (1994) 2683–2690.Google Scholar
  22. 22.
    de Vries, C., Escobedo, J.A., Ueno, H., Houck, K., Ferrara, N. and Williams, L.T., The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor, Science, 255 (1992) 989–991.Google Scholar
  23. 23.
    Terman, B.I., Dougher-Vermazen, M., Carrion, M.E., Dimitrov, D., Armellino, D.C., Gospodarowicz, D. and Bohlen, P., Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor, Biochem. Biophys. Res. Commun., 187 (1992) 1579–1586.Google Scholar
  24. 24.
    Quinn, T.P., Peters, K.G., De Vries, C., Ferrara, N. and Williams, L.T., Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium, Proc. Natl. Acad. Sci. USA, 90 (1993) 7533–7537.Google Scholar
  25. 25.
    Joukov, V., Pajusola, K., Kaipainen, A., Chilov, D., Lahtinen, I., Kukk, E., Saksela, O., Kalkkinen, N. and Alitalo, K., 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 (1996) 290–298.Google Scholar
  26. 26.
    Lee, J., Gray, A., Yuan, J., Luoh, S.M., Avraham, H. and Wood, W.I., Vascular endothelial growth factor-related protein: A ligand and specific activator of the tyrosine kinase receptor Flt4, Proc. Natl. Acad. Sci. USA, 93 (1996) 1988–1992.Google Scholar
  27. 27.
    Achen, M.G., Jeltsch, M., Kukk, E., Makinen, T., Vitali, A., Wilks, A.F., Alitalo, K. and Stacker, S.A., 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, 95 (1998) 548–553.Google Scholar
  28. 28.
    Soker, S., Takashima, S., Miao, H.Q., Neufeld, G. and Klagsbrun, M., Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor, Cell, 92 (1998) 735–745.Google Scholar
  29. 29.
    Gluzman-Poltorak, Z., Cohen, T., Herzog, Y. and Neufeld, G., Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165 [corrected], J. Biol. Chem., 275 (2000) 18040–18045.Google Scholar
  30. 30.
    Leung, D.W., Cachianes, G., Kuang, W.J., Goeddel, D.V. and Ferrara, N., Vascular endothelial growth factor is a secreted angiogenic mitogen, Science, 246 (1989) 1306–1309.Google Scholar
  31. 31.
    Keck, P.J., Hauser, S.D., Krivi, G., Sanzo, K., Warren, T., Feder, J. and Connolly, D.T., Vascular permeability factor, an endothelial cell mitogen related to PDGF, Science, 246 (1989) 1309–1312.Google Scholar
  32. 32.
    Tischer, E., Mitchell, R., Hartman, T., Silva, M., Gospodarowicz, D., Fiddes, J.C. and Abraham, J.A., The human gene for vascular endothelial growth factor: Multiple protein forms are encoded through alternative exon splicing, J. Biol. Chem., 266 (1991) 11947–11954.Google Scholar
  33. 33.
    Poltorak, Z., Cohen, T., Sivan, R., Kandelis, Y., Spira, G., Vlodavsky, I., Keshet, E. and Neufeld, G., VEGF145, a secreted vascular endothelial growth factor isoform that binds to extracellular matrix, J. Biol. Chem., 272 (1997) 7151–7158.Google Scholar
  34. 34.
    Whittle, C., Gillespie, K., Harrison, R., Mathieson, P.W. and Harper, S.J., Heterogeneous vascular endothelial growth factor (VEGF) isoform mRNA and receptor mRNA expression in human glomeruli, and the identification of VEGF148 mRNA, a novel truncated splice variant, Clin. Sci. (Lond), 97 (1999) 303–312.Google Scholar
  35. 35.
    Lange, T., Guttmann-Raviv, N., Baruch, L., Machluf, M. and Neufeld, G., VEGF162, a new heparin-binding vascular endothelial growth factor splice form that is expressed in transformed human cells, J. Biol. Chem., 278 (2003) 17164–17169.Google Scholar
  36. 36.
    Bates, D.O., Cui, T.G., Doughty, J.M., Winkler, M., Sugiono, M., Shields, J.D., Peat, D., Gillatt, D. and Harper, S.J., VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma, Cancer Res., 62 (2002) 4123–4131.Google Scholar
  37. 37.
    Jingjing, L., Xue, Y., Agarwal, N. and Roque, R.S., Human Muller cells express VEGF183, a novel spliced variant of vascular endothelial growth factor, Invest Ophthalmol Vis. Sci., 40 (1999) 752–759.Google Scholar
  38. 38.
    Houck, K.A., Ferrara, N., Winer, J., Cachianes, G., Li, B. and Leung, D.W., The vascular endothelial growth factor family: Identification of a fourth molecular species and characterization of alternative splicing of RNA, Mol. Endocrinol, 5 (1991) 1806–1814.CrossRefGoogle Scholar
  39. 39.
    Vincenti, V., Cassano, C., Rocchi, M. and Persico, G., Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3, Circulation, 93 (1996) 1493–1495.Google Scholar
  40. 40.
    Waltenberger, J., Claesson-Welsh, L., Siegbahn, A., Shibuya, M. and Heldin, C.H., Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor, J. Biol. Chem., 269 (1994) 26988–26995.Google Scholar
  41. 41.
    Millauer, B., Wizigmann-Voos, S., Schnurch, H., Martinez, R., Moller, N.P., Risau, W. and Ullrich, A., High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis, Cell, 72 (1993) 835–846.Google Scholar
  42. 42.
    Shibuya, M., Yamaguchi, S., Yamane, A., Ikeda, T., Tojo, A., Matsushime, H. and Sato, M., Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family, Oncogene, 5 (1990) 519–524.Google Scholar
  43. 43.
    Terman, B.I., Carrion, M.E., Kovacs, E., Rasmussen, B.A., Eddy, R.L. and Shows, T.B., Identification of a new endothelial cell growth factor receptor tyrosine kinase, Oncogene, 6 (1991) 1677–1683.Google Scholar
  44. 44.
    Barleon, B., Totzke, F., Herzog, C., Blanke, S., Kremmer, E., Siemeister, G., Marme, D. and Martiny-Baron, G., Mapping of the sites for ligand binding and receptor dimerization at the extracellular domain of the vascular endothelial growth factor receptor FLT-1, J. Biol. Chem., 272 (1997) 10382–10388.Google Scholar
  45. 45.
    Wiesmann, C., Fuh, G., Christinger, H.W., Eigenbrot, C., Wells, J.A. and de Vos, A.M., Crystal structure at 1.7 a resolution of VEGF in complex with domain 2 of the Flt-1 receptor, Cell, 91 (1997) 695–704.Google Scholar
  46. 46.
    Fuh, G., Li, B., Crowley, C., Cunningham, B. and Wells, J.A., Requirements for binding and signaling of the kinase domain receptor for vascular endothelial growth factor, J. Biol. Chem., 273 (1998) 11197–11204.Google Scholar
  47. 47.
    Shinkai, A., Ito, M., Anazawa, H., Yamaguchi, S., Shitara, K. and Shibuya, M., Mapping of the sites involved in ligand association and dissociation at the extracellular domain of the kinase insert domain-containing receptor for vascular endothelial growth factor, J. Biol. Chem., 273 (1998) 31283–31288.Google Scholar
  48. 48.
    Tao, Q., Backer, M.V., Backer, J.M. and Terman, B.I., Kinase insert domain receptor (KDR) extracellular immunoglobulin-like domains 4–7 contain structural features that block receptor dimerization and vascular endothelial growth factor-induced signaling, J. Biol. Chem., 276 (2001) 21916–21923.Google Scholar
  49. 49.
    Keyt, B.A., Nguyen, H.V., Berleau, L.T., Duarte, C.M., Park, J., Chen, H. and Ferrara, N., 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., 271 (1996) 5638–5646.Google Scholar
  50. 50.
    Li, B., Fuh, G., Meng, G., Xin, X., Gerritsen, M.E., Cunningham, B. and de Vos, A.M., Receptor-selective variants of human vascular endothelial growth factor: Generation and characterization, J. Biol. Chem., 275 (2000) 29823–29828.Google Scholar
  51. 51.
    Pan, B., Li, B., Russell, S.J., Tom, J.Y., Cochran, A.G. and Fairbrother, W.J., Solution structure of a phage-derived peptide antagonist in complex with vascular endothelial growth factor, J. Mol. Biol., 316 (2002) 769–787.Google Scholar
  52. 52.
    Muller, Y.A., Li, B., Christinger, H.W., Wells, J.A., Cunningham, B.C. and de Vos, A.M., Vascular endothelial growth factor: Crystal structure and functional mapping of the kinase domain receptor binding site, Proc. Natl. Acad. Sci. USA, 94 (1997) 7192–7197.Google Scholar
  53. 53.
    Ferrara, N. and Henzel, W.J., Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells, Biochem. Biophys. Res. Commun., 161 (1989) 851–858.Google Scholar
  54. 54.
    He, Z. and Tessier-Lavigne, M., Neuropilin is a receptor for the axonal chemorepellent Semaphorin III, Cell, 90 (1997) 739–751.Google Scholar
  55. 55.
    Kolodkin, A.L., Levengood, D.V., Rowe, E.G., Tai, Y.T., Giger, R.J. and Ginty, D.D., Neuropilin is a semaphorin III receptor, Cell, 90 (1997) 753–762.Google Scholar
  56. 56.
    Chen, H., Chedotal, A., He, Z., Goodman, C.S. and Tessier-Lavigne, M., Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III, Neuron, 19 (1997) 547–559.Google Scholar
  57. 57.
    Mamluk, R., Gechtman, Z., Kutcher, M.E., Gasiunas, N., Gallagher, J. and Klagsbrun, M., Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2, and heparin via its b1b2 domain, J. Biol. Chem., 277 (2002) 24818–24825.Google Scholar
  58. 58.
    Wang, L., Zeng, H., Wang, P., Soker, S. and Mukhopadhyay, D., Neuropilin-1-mediated vascular permeability factor/vascular endothelial growth factor-dependent endothelial cell migration, J. Biol. Chem., 278 (2003) 48848–48860.Google Scholar
  59. 59.
    Houck, K.A., Leung, D.W., Rowland, A.M., Winer, J. and Ferrara, N., Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms, J. Biol. Chem., 267 (1992) 26031–26037.Google Scholar
  60. 60.
    Park, J.E., Keller, G.A. and Ferrara, N., The vascular endothelial growth factor (VEGF) isoforms: Differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF, Mol. Biol. Cell, 4 (1993) 1317–1326.Google Scholar
  61. 61.
    Woolard, J., Wang, W.Y., Bevan, H.S., Qiu, Y., Morbidelli, L., Pritchard-Jones, R.O., Cui, T.G., Sugiono, M., Waine, E., Perrin, R., Foster, R., Digby-Bell, J., Shields, J.D., Whittles, C.E., Mushens, R.E., Gillatt, D.A., Ziche, M., Harper, S.J. and Bates, D.O., VEGF165b, an inhibitory vascular endothelial growth factor splice variant: Mechanism of action, in vivo effect on angiogenesis and endogenous protein expression, Cancer Res., 64 (2004) 7822–7835.Google Scholar
  62. 62.
    Tessler, S., Rockwell, P., Hicklin, D., Cohen, T., Levi, B.Z., Witte, L., Lemischka, I.R. and Neufeld, G., Heparin modulates the interaction of VEGF165 with soluble and cell associated flk-1 receptors, J. Biol. Chem., 269 (1994) 12456–12461.Google Scholar
  63. 63.
    Gitay-Goren, H., Cohen, T., Tessler, S., Soker, S., Gengrinovitch, S., Rockwell, P., Klagsbrun, M., Levi, B.Z. and Neufeld, G., Selective binding of VEGF121 to one of the three vascular endothelial growth factor receptors of vascular endothelial cells, J. Biol. Chem., 271 (1996) 5519–5523.Google Scholar
  64. 64.
    Cohen, T., Gitay-Goren, H., Sharon, R., Shibuya, M., Halaban, R., Levi, B.Z. and Neufeld, G., VEGF121, a vascular endothelial growth factor (VEGF) isoform lacking heparin binding ability, requires cell-surface heparan sulfates for efficient binding to the VEGF receptors of human melanoma cells, J. Biol. Chem., 270 (1995) 11322–11326.Google Scholar
  65. 65.
    Keyt, B.A., Berleau, L.T., Nguyen, H.V., Chen, H., Heinsohn, H., Vandlen, R. and Ferrara, N., The carboxyl-terminal domain (111–165) of vascular endothelial growth factor is critical for its mitogenic potency, J. Biol. Chem., 271 (1996) 7788–7795.Google Scholar
  66. 66.
    Fairbrother, W.J., Champe, M.A., Christinger, H.W., Keyt, B.A. and Starovasnik, M.A., Solution structure of the heparin-binding domain of vascular endothelial growth factor, Structure, 6 (1998) 637–648.Google Scholar
  67. 67.
    Shweiki, D., Itin, A., Soffer, D. and Keshet, E., Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis, Nature, 359 (1992) 843–845.Google Scholar
  68. 68.
    Stein, I., Neeman, M., Shweiki, D., Itin, A. and Keshet, E., Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes, Mol. Cell Biol., 15 (1995) 5363–5368.Google Scholar
  69. 69.
    Ikeda, E., Achen, M.G., Breier, G. and Risau, W., Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells, J. Biol. Chem., 270 (1995) 19761–19766.Google Scholar
  70. 70.
    Pugh, C.W. and Ratcliffe, P.J., Regulation of angiogenesis by hypoxia: Role of the HIF system, Nat. Med., 9 (2003) 677–684.Google Scholar
  71. 71.
    Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J.M., Lane, W.S. and Kaelin, W.G., Jr., HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing, Science, 292 (2001) 464–468.Google Scholar
  72. 72.
    Jaakkola, P., Mole, D.R., Tian, Y.M., Wilson, M.I., Gielbert, J., Gaskell, S.J., Kriegsheim, A., Hebestreit, H.F., Mukherji, M., Schofield, C.J., Maxwell, P.H., Pugh, C.W. and Ratcliffe, P.J., Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation, Science, 292 (2001) 468–472.Google Scholar
  73. 73.
    Yu, F., White, S.B., Zhao, Q. and Lee, F.S., HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation, Proc. Natl. Acad. Sci. USA, 98 (2001) 9630–9635.Google Scholar
  74. 74.
    Masson, N., Willam, C., Maxwell, P.H., Pugh, C.W. and Ratcliffe, P.J., Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation, EMBO J., 20 (2001) 5197–5206.Google Scholar
  75. 75.
    Hiratsuka, S., Minowa, O., Kuno, J., Noda, T. and Shibuya, M., Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice, Proc. Natl. Acad. Sci. USA, 95 (1998) 9349–9354.Google Scholar
  76. 76.
    Fong, G.H., Zhang, L., Bryce, D.M. and Peng, J., Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice, Development, 126 (1999) 3015–3025.Google Scholar
  77. 77.
    Zeng, H., Dvorak, H.F. and Mukhopadhyay, D., Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) peceptor-1 down-modulates VPF/VEGF receptor-2-mediated endothelial cell proliferation, but not migration, through phosphatidylinositol 3-kinase-dependent pathways, J. Biol. Chem., 276 (2001) 26969–26979.Google Scholar
  78. 78.
    Gille, H., Kowalski, J., Yu, L., Chen, H., Pisabarro, M.T., Davis-Smyth, T. and Ferrara, N., A repressor sequence in the juxtamembrane domain of Flt-1 (VEGFR-1) constitutively inhibits vascular endothelial growth factor-dependent phosphatidylinositol 3′-kinase activation and endothelial cell migration, EMBO J., 19 (2000) 4064–4073.Google Scholar
  79. 79.
    Barleon, B., Sozzani, S., Zhou, D., Weich, H.A., Mantovani, A. and Marme, D., Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1, Blood, 87 (1996) 3336–3343.Google Scholar
  80. 80.
    LeCouter, J., Moritz, D.R., Li, B., Phillips, G.L., Liang, X.H., Gerber, H.P., Hillan, K.J. and Ferrara, N., Angiogenesis-independent endothelial protection of liver: Role of VEGFR-1, Science, 299 (2003) 890–893.Google Scholar
  81. 81.
    Rissanen, T.T., Markkanen, J.E., Gruchala, M., Heikura, T., Puranen, A., Kettunen, M.I., Kholova, I., Kauppinen, R.A., Achen, M.G., Stacker, S.A., Alitalo, K. and Yla-Herttuala, S., VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses, Circ. Res., 92 (2003) 1098–1106.Google Scholar
  82. 82.
    Nagy, J.A., Vasile, E., Feng, D., Sundberg, C., Brown, L.F., Detmar, M.J., Lawitts, J.A., Benjamin, L., Tan, X., Manseau, E.J., Dvorak, A.M. and Dvorak, H.F., Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis, J. Exp. Med., 196 (2002) 1497–1506.Google Scholar
  83. 83.
    Nagy, J.A., Vasile, E., Feng, D., Sundberg, C., Brown, L.F., Manseau, E.J., Dvorak, A.M. and Dvorak, H.F., VEGF-A induces angiogenesis, arteriogenesis, lymphangiogenesis, and vascular malformations, Cold Spring. Harb. Symp. Quant. Biol., 67 (2002) 227–237.Google Scholar
  84. 84.
    Olofsson, B., Pajusola, K., Kaipainen, A., von Euler, G., Joukov, V., Saksela, O., Orpana, A., Pettersson, R.F., Alitalo, K. and Eriksson, U., Vascular endothelial growth factor B, a novel growth factor for endothelial cells, Proc. Natl. Acad. Sci. USA, 93 (1996) 2576–2581.Google Scholar
  85. 85.
    Aase, K., Lymboussaki, A., Kaipainen, A., Olofsson, B., Alitalo, K. and Eriksson, U., Localization of VEGF-B in the mouse embryo suggests a paracrine role of the growth factor in the developing vasculature, Dev. Dyn., 215 (1999) 12–25.Google Scholar
  86. 86.
    Olofsson, B., Korpelainen, E., Pepper, M.S., Mandriota, S.J., Aase, K., Kumar, V., Gunji, Y., Jeltsch, M.M., Shibuya, M., Alitalo, K. and Eriksson, U., 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, 95 (1998) 11709–11714.Google Scholar
  87. 87.
    Paavonen, K., Horelli-Kuitunen, N., Chilov, D., Kukk, E., Pennanen, S., Kallioniemi, O.P., Pajusola, K., Olofsson, B., Eriksson, U., Joukov, V., Palotie, A. and Alitalo, K., Novel human vascular endothelial growth factor genes VEGF-B and VEGF-C localize to chromosomes 11q13 and 4q34, respectively, Circulation, 93 (1996) 1079–1082.Google Scholar
  88. 88.
    Olofsson, B., Pajusola, K., von Euler, G., Chilov, D., Alitalo, K. and Eriksson, U., Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform, J. Biol. Chem., 271 (1996) 19310–19317.Google Scholar
  89. 89.
    Makinen, T., Olofsson, B., Karpanen, T., Hellman, U., Soker, S., Klagsbrun, M., Eriksson, U. and Alitalo, K., Differential binding of vascular endothelial growth factor B splice and proteolytic isoforms to neuropilin-1, J. Biol. Chem., 274 (1999) 21217–21222.Google Scholar
  90. 90.
    Guillin, M.C., Bezeaud, A., Bouton, M.C. and Jandrot-Perrus, M., Thrombin specificity, Thromb Haemost, 74 (1995) 129–133.Google Scholar
  91. 91.
    Louzier, V., Raffestin, B., Leroux, A., Branellec, D., Caillaud, J.M., Levame, M., Eddahibi, S. and Adnot, S., Role of VEGF-B in the lung during development of chronic hypoxic pulmonary hypertension, Am. J. Physiol. Lung. Cell. Mol. Physiol., 284 (2003) L926–937.Google Scholar
  92. 92.
    Silvestre, J.S., Tamarat, R., Ebrahimian, T.G., Le-Roux, A., Clergue, M., Emmanuel, F., Duriez, M., Schwartz, B., Branellec, D. and Levy, B.I., Vascular endothelial growth factor-B promotes in vivo angiogenesis, Circ. Res., 93 (2003) 114–123.Google Scholar
  93. 93.
    Bellomo, D., Headrick, J.P., Silins, G.U., Paterson, C.A., Thomas, P.S., Gartside, M., Mould, A., Cahill, M.M., Tonks, I.D., Grimmond, S.M., Townson, S., Wells, C., Little, M., Cummings, M.C., Hayward, N.K. and Kay, G.F., 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 (2000) E29–35.Google Scholar
  94. 94.
    Aase, K., von Euler, G., Li, X., Ponten, A., Thoren, P., Cao, R., Cao, Y., Olofsson, B., Gebre-Medhin, S., Pekny, M., Alitalo, K., Betsholtz, C. and Eriksson, U., Vascular endothelial growth factor-B-deficient mice display an atrial conduction defect, Circulation, 104 (2001) 358–364.Google Scholar
  95. 95.
    Yoon, Y.S. and Losordo, D.W., All in the family: VEGF-B joins the ranks of proangiogenic cytokines, Circ. Res., 93 (2003) 87–90.Google Scholar
  96. 96.
    Eriksson, U. and Alitalo, K., Structure, expression and receptor-binding properties of novel vascular endothelial growth factors, Curr. Top. Microbiol. Immunol., 237 (1999) 41–57.Google Scholar
  97. 97.
    Miquerol, L., Gertsenstein, M., Harpal, K., Rossant, J. and Nagy, A., Multiple developmental roles of VEGF suggested by a LacZ-tagged allele, Dev. Biol., 212 (1999) 307–322.Google Scholar
  98. 98.
    Maglione, D., Guerriero, V., Viglietto, G., Delli-Bovi, P. and Persico, M.G., Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor, Proc. Natl. Acad. Sci. USA, 88 (1991) 9267–9271.Google Scholar
  99. 99.
    Persico, M.G., Vincenti, V. and DiPalma, T., Structure, expression and receptor-binding properties of placenta growth factor (PlGF), Curr. Top. Microbiol. Immunol., 237 (1999) 31–40.Google Scholar
  100. 100.
    Park, J.E., Chen, H.H., Winer, J., Houck, K.A. and 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 (1994) 25646–25654.Google Scholar
  101. 101.
    Iyer, S., Leonidas, D.D., Swaminathan, G.J., Maglione, D., Battisti, M., Tucci, M., Persico, M.G. and Acharya, K.R., The crystal structure of human placenta growth factor-1 (PlGF-1), an angiogenic protein, at 2.0 a resolution, J. Biol. Chem., 276 (2001) 12153–12161.Google Scholar
  102. 102.
    Christinger, H.W., Fuh, G., de Vos, A.M. and Wiesmann, C., The crystal structure of placental growth factor in complex with domain 2 of vascular endothelial growth factor receptor-1, J. Biol. Chem., 279 (2004) 10382–10388.Google Scholar
  103. 103.
    Errico, M., Riccioni, T., Iyer, S., Pisano, C., Acharya, K.R., Persico, M.G. and De Falco, S., Identification of placenta growth factor determinants for binding and activation of Flt-1 receptor, J. Biol. Chem., 279 (2004) 43929–43939.Google Scholar
  104. 104.
    Maglione, D., Guerriero, V., Viglietto, G., Ferraro, M.G., Aprelikova, O., Alitalo, K., Del Vecchio, S., Lei, K.J., Chou, J.Y. and Persico, M.G., Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14, Oncogene, 8 (1993) 925–931.Google Scholar
  105. 105.
    Cao, Y., Ji, W.R., Qi, P. and Rosin, A., Placenta growth factor: Identification and characterization of a novel isoform generated by RNA alternative splicing, Biochem. Biophys. Res. Commun., 235 (1997) 493–498.Google Scholar
  106. 106.
    Yang, W., Ahn, H., Hinrichs, M., Torry, R.J. and Torry, D.S., Evidence of a novel isoform of placenta growth factor (PlGF-4) expressed in human trophoblast and endothelial cells, J. Reprod. Immunol., 60 (2003) 53–60.Google Scholar
  107. 107.
    Hauser, S. and Weich, H.A., A heparin-binding form of placenta growth factor (PlGF-2) is expressed in human umbilical vein endothelial cells and in placenta, Growth Factors, 9 (1993) 259–268.CrossRefGoogle Scholar
  108. 108.
    Migdal, M., Huppertz, B., Tessler, S., Comforti, A., Shibuya, M., Reich, R., Baumann, H. and Neufeld, G., Neuropilin-1 is a placenta growth factor-2 receptor, J. Biol. Chem., 273 (1998) 22272–22278.Google Scholar
  109. 109.
    Luttun, A., Tjwa, M., Moons, L., Wu, Y., Angelillo-Scherrer, A., Liao, F., Nagy, J.A., Hooper, A., Priller, J., De Klerck, B., Compernolle, V., Daci, E., Bohlen, P., Dewerchin, M., Herbert, J.M., Fava, R., Matthys, P., Carmeliet, G., Collen, D., Dvorak, H.F., Hicklin, D.J. and Carmeliet, P., Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1, Nat. Med., 8 (2002) 831–840.Google Scholar
  110. 110.
    Autiero, M., Waltenberger, J., Communi, D., Kranz, A., Moons, L., Lambrechts, D., Kroll, J., Plaisance, S., De Mol, M., Bono, F., Kliche, S., Fellbrich, G., Ballmer-Hofer, K., Maglione, D., Mayr-Beyrle, U., Dewerchin, M., Dombrowski, S., Stanimirovic, D., Van Hummelen, P., Dehio, C., Hicklin, D.J., Persico, G., Herbert, J.M., Shibuya, M., Collen, D., Conway, E.M. and Carmeliet, P., Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1, Nat. Med., 9 (2003) 936–943.Google Scholar
  111. 111.
    DiSalvo, J., Bayne, M.L., Conn, G., Kwok, P.W., Trivedi, P.G., Soderman, D.D., Palisi, T.M., Sullivan, K.A. and Thomas, K.A., Purification and characterization of a naturally occurring vascular endothelial growth factor.placenta growth factor heterodimer, J. Biol. Chem., 270 (1995) 7717–7723.Google Scholar
  112. 112.
    Cao, Y., Chen, H., Zhou, L., Chiang, M.K., Anand-Apte, B., Weatherbee, J.A., Wang, Y., Fang, F., Flanagan, J.G. and Tsang, M.L., Heterodimers of placenta growth factor/vascular endothelial growth factor. Endothelial activity, tumor cell expression, and high affinity binding to Flk-1/KDR, J. Biol. Chem., 271 (1996) 3154–3162.Google Scholar
  113. 113.
    Eriksson, A., Cao, R., Pawliuk, R., Berg, S.M., Tsang, M., Zhou, D., Fleet, C., Tritsaris, K., Dissing, S., Leboulch, P. and Cao, Y., Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers, Cancer Cell, 1 (2002) 99–108.Google Scholar
  114. 114.
    Carmeliet, P., Moons, L., Luttun, A., Vincenti, V., Compernolle, V., De Mol, M., Wu, Y., Bono, F., Devy, L., Beck, H., Scholz, D., Acker, T., DiPalma, T., Dewerchin, M., Noel, A., Stalmans, I., Barra, A., Blacher, S., Vandendriessche, T., Ponten, A., Eriksson, U., Plate, K.H., Foidart, J.M., Schaper, W., Charnock-Jones, D.S., Hicklin, D.J., Herbert, J.M., Collen, D. and Persico, M.G., Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions, Nat. Med., 7 (2001) 575–583.Google Scholar
  115. 115.
    Odorisio, T., Schietroma, C., Zaccaria, M.L., Cianfarani, F., Tiveron, C., Tatangelo, L., Failla, C.M. and Zambruno, G., Mice overexpressing placenta growth factor exhibit increased vascularization and vessel permeability, J. Cell Sci., 115 (2002) 2559–2567.Google Scholar
  116. 116.
    Oura, H., Bertoncini, J., Velasco, P., Brown, L.F., Carmeliet, P. and Detmar, M., A critical role of placental growth factor in the induction of inflammation and edema formation, Blood, 101 (2003) 560–567.Google Scholar
  117. 117.
    Veikkola, T., Jussila, L., Makinen, T., Karpanen, T., Jeltsch, M., Petrova, T.V., Kubo, H., Thurston, G., McDonald, D.M., Achen, M.G., Stacker, S.A. and Alitalo, K., Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice, EMBO J., 20 (2001) 1223–1231.Google Scholar
  118. 118.
    Baldwin, M.E., Roufail, S., Halford, M.M., Alitalo, K., Stacker, S.A. and Achen, M.G., Multiple forms of mouse vascular endothelial growth factor-D are generated by RNA splicing and proteolysis, J. Biol. Chem., 276 (2001) 44307–44314.Google Scholar
  119. 119.
    Joukov, V., Sorsa, T., Kumar, V., Jeltsch, M., Claesson-Welsh, L., Cao, Y., Saksela, O., Kalkkinen, N. and Alitalo, K., Proteolytic processing regulates receptor specificity and activity of VEGF-C, EMBO J., 16 (1997) 3898–3911.Google Scholar
  120. 120.
    Makinen, T., Veikkola, T., Mustjoki, S., Karpanen, T., Catimel, B., Nice, E.C., Wise, L., Mercer, A., Kowalski, H., Kerjaschki, D., Stacker, S.A., Achen, M.G. and Alitalo, K., Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3, EMBO J., 20 (2001) 4762–4773.Google Scholar
  121. 121.
    Stacker, S.A., Stenvers, K., Caesar, C., Vitali, A., Domagala, T., Nice, E., Roufail, S., Simpson, R.J., Moritz, R., Karpanen, T., Alitalo, K. and Achen, M.G., Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers, J. Biol. Chem., 274 (1999) 32127–32136.Google Scholar
  122. 122.
    Baldwin, M.E., Catimel, B., Nice, E.C., Roufail, S., Hall, N.E., Stenvers, K.L., Karkkainen, M.J., Alitalo, K., Stacker, S.A. and Achen, M.G., The specificity of receptor binding by vascular endothelial growth factor-d is different in mouse and man, J. Biol. Chem., 276 (2001) 19166–19171.Google Scholar
  123. 123.
    McColl, B.K., Baldwin, M.E., Roufail, S., Freeman, C., Moritz, R.L., Simpson, R.J., Alitalo, K., Stacker, S.A. and Achen, M.G., Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D, J. Exp. Med., 198 (2003) 863–868.Google Scholar
  124. 124.
    Siegfried, G., Basak, A., Cromlish, J.A., Benjannet, S., Marcinkiewicz, J., Chretien, M., Seidah, N.G. and Khatib, A.M., The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis, J. Clin. Invest., 111 (2003) 1723–1732.Google Scholar
  125. 125.
    Joukov, V., Kumar, V., Sorsa, T., Arighi, E., Weich, H., Saksela, O. and Alitalo, K., 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., 273 (1998) 6599–6602.Google Scholar
  126. 126.
    Stacker, S.A., Vitali, A., Caesar, C., Domagala, T., Groenen, L.C., Nice, E., Achen, M.G. and Wilks, A.F., 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 (1999) 34884–34892.Google Scholar
  127. 127.
    Veikkola, T., Karkkainen, M., Claesson-Welsh, L. and Alitalo, K., Regulation of angiogenesis via vascular endothelial growth factor receptors, Cancer Res., 60 (2000) 203–212.Google Scholar
  128. 128.
    Eliceiri, B.P., Paul, R., Schwartzberg, P.L., Hood, J.D., Leng, J. and Cheresh, D.A., Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability, Mol. Cell, 4 (1999) 915–924.Google Scholar
  129. 129.
    Weis, S.M. and Cheresh, D.A., Pathophysiological consequences of VEGF-induced vascular permeability, Nature, 437 (2005) 497–504.Google Scholar
  130. 130.
    Eliceiri, B.P., Puente, X.S., Hood, J.D., Stupack, D.G., Schlaepfer, D.D., Huang, X.Z., Sheppard, D. and Cheresh, D.A., Src-mediated coupling of focal adhesion kinase to integrin alpha(v)beta5 in vascular endothelial growth factor signaling, J. Cell Biol., 157 (2002) 149–160.Google Scholar
  131. 131.
    Robinson, S.D., Reynolds, L.E., Wyder, L., Hicklin, D.J. and Hodivala-Dilke, K.M., Beta3-integrin regulates vascular endothelial growth factor-A-dependent permeability, Arterioscler. Thromb. Vasc. Biol., 24 (2004) 2108–2114.Google Scholar
  132. 132.
    Borges, E., Jan, Y. and Ruoslahti, E., Platelet-derived growth factor receptor beta and vascular endothelial growth factor receptor 2 bind to the beta 3 integrin through its extracellular domain, J. Biol. Chem., 275 (2000) 39867–39873.Google Scholar
  133. 133.
    Karkkainen, M.J., Haiko, P., Sainio, K., Partanen, J., Taipale, J., Petrova, T.V., Jeltsch, M., Jackson, D.G., Talikka, M., Rauvala, H., Betsholtz, C. and Alitalo, K., Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins, Nat. Immunol., 5 (2004) 74–80.Google Scholar
  134. 134.
    Baldwin, M.E., Halford, M.M., Roufail, S., Williams, R.A., Hibbs, M.L., Grail, D., Kubo, H., Stacker, S.A. and Achen, M.G., Vascular endothelial growth factor D is dispensable for development of the lymphatic system, Mol. Cell Biol., 25 (2005) 2441–2449.Google Scholar
  135. 135.
    Karkkainen, M.J., Saaristo, A., Jussila, L., Karila, K.A., Lawrence, E.C., Pajusola, K., Bueler, H., Eichmann, A., Kauppinen, R., Kettunen, M.I., Yla-Herttuala, S., Finegold, D.N., Ferrell, R.E. and Alitalo, K., A model for gene therapy of human hereditary lymphedema, Proc. Natl. Acad. Sci. USA, 98 (2001) 12677–12682.Google Scholar
  136. 136.
    Yuan, L., Moyon, D., Pardanaud, L., Breant, C., Karkkainen, M.J., Alitalo, K. and Eichmann, A., Abnormal lymphatic vessel development in neuropilin 2 mutant mice, Development, 129 (2002) 4797–4806.Google Scholar
  137. 137.
    Lyttle, D.J., Fraser, K.M., Fleming, S.B., Mercer, A.A. and Robinson, A.J., Homologs of vascular endothelial growth factor are encoded by the poxvirus orf virus, J. Virol, 68 (1994) 84–92.Google Scholar
  138. 138.
    Mercer, A.A., Wise, L.M., Scagliarini, A., McInnes, C.J., Buttner, M., Rziha, H.J., McCaughan, C.A., Fleming, S.B., Ueda, N. and Nettleton, P.F., Vascular endothelial growth factors encoded by Orf virus show surprising sequence variation but have a conserved, functionally relevant structure, J. Gen. Virol, 83 (2002) 2845–2855.Google Scholar
  139. 139.
    Ueda, N., Wise, L.M., Stacker, S.A., Fleming, S.B. and Mercer, A.A., Pseudocowpox virus encodes a homolog of vascular endothelial growth factor, Virology, 305 (2003) 298–309.Google Scholar
  140. 140.
    Wise, L.M., Veikkola, T., Mercer, A.A., Savory, L.J., Fleming, S.B., Caesar, C., Vitali, A., Makinen, T., Alitalo, K. and Stacker, S.A., Vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1, Proc. Natl. Acad. Sci. USA, 96 (1999) 3071–3076.Google Scholar
  141. 141.
    Ogawa, S., Oku, A., Sawano, A., Yamaguchi, S., Yazaki, Y. and Shibuya, M., 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., 273 (1998) 31273–31282.Google Scholar
  142. 142.
    Meyer, M., Clauss, M., Lepple-Wienhues, A., Waltenberger, J., Augustin, H.G., Ziche, M., Lanz, C., Buttner, M., Rziha, H.J. and Dehio, C., A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signaling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases, EMBO J., 18 (1999) 363–374.Google Scholar
  143. 143.
    Shibuya, M., Vascular endothelial growth factor receptor-2: Its unique signaling and specific ligand, VEGF-E, Cancer Sci., 94 (2003) 751–756.Google Scholar
  144. 144.
    Wise, L.M., Ueda, N., Dryden, N.H., Fleming, S.B., Caesar, C., Roufail, S., Achen, M.G., Stacker, S.A. and Mercer, A.A., Viral vascular endothelial growth factors vary extensively in amino acid sequence, receptor-binding specificities, and the ability to induce vascular permeability yet are uniformly active mitogens, J. Biol. Chem., 278 (2003) 38004–38014.Google Scholar
  145. 145.
    Savory, L.J., Stacker, S.A., Fleming, S.B., Niven, B.E. and Mercer, A.A., Viral vascular endothelial growth factor plays a critical role in orf virus infection, J. Virol., 74 (2000) 10699–10706.Google Scholar
  146. 146.
    Komori, Y., Nikai, T., Taniguchi, K., Masuda, K. and Sugihara, H., Vascular endothelial growth factor VEGF-like heparin-binding protein from the venom of Vipera aspis aspis (Aspic viper), Biochemistry, 38 (1999) 11796–11803.Google Scholar
  147. 147.
    Yamazaki, Y., Takani, K., Atoda, H. and Morita, T., Snake venom vascular endothelial growth factors (VEGFs) exhibit potent activity through their specific recognition of KDR (VEGF receptor 2), J. Biol. Chem., 278 (2003) 51985–51988.Google Scholar
  148. 148.
    Suto, K., Yamazaki, Y., Morita, T. and Mizuno, H., Crystal structures of novel vascular endothelial growth factors (VEGF) from snake venoms: Insight into selective VEGF binding to kinase insert domain-containing receptor but not to fms-like tyrosine kinase-1, J. Biol. Chem., 280 (2005) 2126–2131.Google Scholar
  149. 149.
    Junqueira de Azevedo, I.L., Farsky, S.H., Oliveira, M.L. and Ho, P.L., Molecular cloning and expression of a functional snake venom vascular endothelium growth factor (VEGF) from the Bothrops insularis pit viper. A new member of the VEGF family of proteins, J. Biol. Chem., 276 (2001) 39836–39842.Google Scholar
  150. 150.
    Gasmi, A., Bourcier, C., Aloui, Z., Srairi, N., Marchetti, S., Gimond, C., Wedge, S.R., Hennequin, L. and Pouyssegur, J., Complete structure of an increasing capillary permeability protein (ICPP) purified from Vipera lebetina venom. ICPP is angiogenic via vascular endothelial growth factor receptor signalling, J. Biol. Chem., 277 (2002) 29992–29998.Google Scholar
  151. 151.
    Takahashi, H., Hattori, S., Iwamatsu, A., Takizawa, H. and Shibuya, M., A novel snake venom vascular endothelial growth factor (VEGF) predominantly induces vascular permeability through preferential signaling via VEGF receptor-1, J. Biol. Chem., 279 (2004) 46304–46314.Google Scholar
  152. 152.
    Chen, Y.L., Tsai, I.H., Hong, T.M. and Tsai, S.H., Crotalid venom vascular endothelial growth factors has preferential affinity for VEGFR-1. Characterization of Protobothrops mucrosquamatus venom VEGF, Thromb. Haemost., 93 (2005) 331–338.Google Scholar
  153. 153.
    Tokunaga, Y., Yamazaki, Y. and Morita, T., Specific distribution of VEGF-F in Viperinae snake venoms: Isolation and characterization of a VGEF-F from the venom of Daboia russelli siamensis, Arch. Biochem. Biophys., 439 (2005) 241–247.Google Scholar
  154. 154.
    Yamazaki, Y., Tokunaga, Y., Takani, K. and Morita, T., Identification of the heparin-binding region of snake venom vascular endothelial growth factor (VEGF-F) and its blocking of VEGF-A165, Biochemistry, 44 (2005) 8858–8864.Google Scholar
  155. 155.
    Francischetti, I.M., My-Pham, V., Harrison, J., Garfield, M.K. and Ribeiro, J.M., Bitis gabonica (Gaboon viper) snake venom gland: Toward a catalog for the full-length transcripts (cDNA) and proteins, Gene, 337 (2004) 55–69.Google Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Department of BiochemistryMeiji Pharmaceutical UniversityKiyoseJapan

Personalised recommendations