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The Biology of Vascular Endothelial Cell Growth Factor Isoforms

  • Yin-Shan Ng
Part of the Molecular Biology Intelligence Unit book series (MBIU)

Abstract

The field of angiogenesis research was literally transformed overnight by the discovery of vascular endothelial growth factor (VEGF). Researchers quickly embraced VEGF in their different areas of vascular and angiogenesis research, and in the last two decades have discovered much about VEGF biology. It is now clear that VEGF is actually a collection of different isoforms. Through differential pre-mRNA splicing and protein processing, one VEGF gene gives rise to several different protein isoforms, which together orchestrate the complex processes of angiogenesis, vessel growth and adult vascular functions. The VEGF isoforms differ biochemically, and genetic experiments in mice have proven that the isoforms have different functions. Furthermore, certain VEGF isoforms associate with and likely play differential roles in various pathologic states. With better understanding of VEGF isoform biology, new insights into the complex mechanisms of VEGF-mediated vessel growth can be gained. In addition, findings about the specific VEGF isoform functions have important implications for VEGF-mediated therapeutic angiogenesis as well as anti-angiogenic therapy targeting VEGF.

Keywords

Vascular Endothelial Growth Factor Vascular Development Vascular Endothelial Growth Factor Pathway Inhibitory Vascular Endothelial Growth Vascular Endothelial Growth Factor 165b 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002; 29(6 Suppl 16):15–18.PubMedGoogle Scholar
  2. 2.
    Senger DR, Connolly DT, Van de Water L et al. Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res 1990; 50(6):1774–1778.PubMedGoogle Scholar
  3. 3.
    Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 1989; 161(2):851–858.PubMedCrossRefGoogle Scholar
  4. 4.
    Ferrara N. Vascular endothelial growth factor: Basic science and clinical progress. Endocr Rev 2004; 25(4):581–611.PubMedCrossRefGoogle Scholar
  5. 5.
    Cho NK, Keyes L, Johnson E et al. Developmental control of blood cell migration by the Drosophila VEGF pathway. Cell 2002; 108(6):865–876.PubMedCrossRefGoogle Scholar
  6. 6.
    Cleaver O, Krieg PA. VEGF mediates angioblast migration during development of the dorsal aorta in Xenopus. Development 1998; 125(19):3905–3914.PubMedGoogle Scholar
  7. 7.
    Liang D, Chang JR, Chin AJ et al. The role of vascular endothelial growth factor (VEGF) in vasculogenesis, angiogenesis, and hematopoiesis in zebrafish development. Mech Dev 2001; 108(1–2):29–43.PubMedCrossRefGoogle Scholar
  8. 8.
    Traver D, Zon LI. Walking the walk: Migration and other common themes in blood and vascular development. Cell 2002; 108(6):731–734.PubMedCrossRefGoogle Scholar
  9. 9.
    Breier G, Albrecht U, Sterrer S et al. Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development 1992; 114(2):521–532.PubMedGoogle Scholar
  10. 10.
    Millauer B, Wizigmann-Voos S, Schnurch H et al. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 1993; 72(6):835–846.PubMedCrossRefGoogle Scholar
  11. 11.
    Fong GH, Rossant J, Gertsenstein M et al. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 1995; 376(6535):66–70.PubMedCrossRefGoogle Scholar
  12. 12.
    Shalaby F, Rossant J, Yamaguchi TP et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995; 376(6535):62–66.PubMedCrossRefGoogle Scholar
  13. 13.
    Carmeliet P, Ferreira V, Breier G et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996; 380(6573):435–439.PubMedCrossRefGoogle Scholar
  14. 14.
    Ferrara N, Carver-Moore K, Chen H et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996; 380(6573):439–442.PubMedCrossRefGoogle Scholar
  15. 15.
    Miquerol L, Langille BL, Nagy A. Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression. Development 2000; 127(18):3941–3946.PubMedGoogle Scholar
  16. 16.
    Kim KJ, Li B, Winer J et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993; 362(6423):841–844.PubMedCrossRefGoogle Scholar
  17. 17.
    Millauer B, Shawver LK, Plate KH et al. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 1994; 367(6463):576–579.PubMedCrossRefGoogle Scholar
  18. 18.
    Adamis AP, Shima DT, Tolentino MJ et al. Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch Ophthalmol 1996; 114(1):66–71.PubMedGoogle Scholar
  19. 19.
    Ferrara N. Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol 2001; 280(6):C1358–1366.PubMedGoogle Scholar
  20. 20.
    Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1(1):27–31.PubMedCrossRefGoogle Scholar
  21. 21.
    Adamis AP, Shima DT. The role of vascular endothelial growth factor in ocular health and disease. Retina 2005; 25(2):111–118.PubMedCrossRefGoogle Scholar
  22. 22.
    Holmes DI, Zachary I. The vascular endothelial growth factor (VEGF) family: Angiogenic factors in health and disease. Genome Biol 2005; 6(2):209.PubMedCrossRefGoogle Scholar
  23. 23.
    Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 2001; 114 (Pt 5):853–865.PubMedGoogle Scholar
  24. 24.
    Soker S, Takashima S, Miao HQ et al. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998; 92(6):735–745.PubMedCrossRefGoogle Scholar
  25. 25.
    Tischer E, Mitchell R, Hartman T et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 1991; 266(18):11947–11954.PubMedGoogle Scholar
  26. 26.
    Ng YS, Rohan R, Sunday ME et al. Differential expression of VEGF isoforms in mouse during development and in the adult. Dev Dyn 2001; 220(2):112–121.PubMedCrossRefGoogle Scholar
  27. 27.
    Miquerol L, Gertsenstein M, Harpal K et al. Multiple developmental roles of VEGF suggested by a LacZ-tagged allele. Dev Biol 1999; 212(2):307–322.PubMedCrossRefGoogle Scholar
  28. 28.
    Houck KA, Leung DW, Rowland AM et al. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 1992; 267(36):26031–26037.PubMedGoogle Scholar
  29. 29.
    Bergers G, Brekken R, McMahon G et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2000; 2(10):737–744.PubMedCrossRefGoogle Scholar
  30. 30.
    Engsig MT, Chen QJ, Vu TH et al. Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones. J Cell Biol 2000; 151(4):879–889.PubMedCrossRefGoogle Scholar
  31. 31.
    Iruela-Arispe ML, Carpizo D, Luque A. ADAMTS1: A matrix metalloprotease with angioinhibitory properties. Ann NY Acad Sci 2003; 995:183–190.PubMedCrossRefGoogle Scholar
  32. 32.
    Lee S, Jilani SM, Nikolova GV et al. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol 2005; 169(4):681–691.PubMedCrossRefGoogle Scholar
  33. 33.
    Whitaker GB, Limberg BJ, Rosenbaum JS. Vascular endothelial growth factor receptor-2 and neuropilin-1 form a receptor complex that is responsible for the differential signaling potency of VEGF(165) and VEGF(121). J Biol Chem 2001; 276(27):25520–25531.PubMedCrossRefGoogle Scholar
  34. 34.
    Bachelder RE, Crago A, Chung J et al. Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells. Cancer Res 2001; 61(15):5736–5740.PubMedGoogle Scholar
  35. 35.
    Wang L, Zeng H, Wang P et al. Neuropilin-1-mediated vascular permeability factor/vascular endothelial growth factor-dependent endothelial cell migration. J Biol Chem 2003; 278(49):48848–48860.PubMedCrossRefGoogle Scholar
  36. 36.
    Kawasaki T, Kitsukawa T, Bekku Y et al. A requirement for neuropilin-1 in embryonic vessel formation. Development 1999; 126(21):4895–4902.PubMedGoogle Scholar
  37. 37.
    Gerhardt H, Ruhrberg C, Abramsson A et al. Neuropilin-1 is required for endothelial tip cell guidance in the developing central nervous system. Dev Dyn 2004; 231(3):503–509.PubMedCrossRefGoogle Scholar
  38. 38.
    Gluzman-Poltorak Z, Cohen T, Herzog Y et al. Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165 [corrected]. J Biol Chem 2000; 275(24):18040–18045.PubMedCrossRefGoogle Scholar
  39. 39.
    Carmeliet P, Ng YS, Nuyens D et al. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF 164 and VEGF 188. Nat Med 1999; 5(5):495–502.PubMedCrossRefGoogle Scholar
  40. 40.
    Stalmans I, Ng YS, Rohan R et al. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest 2002; 109(3):327–336.PubMedGoogle Scholar
  41. 41.
    Cheng SY, Nagane M, Huang HS et al. Intracerebral tumor-associated hemorrhage caused by overexpression of the vascular endothelial growth factor isoforms VEGF 121 and VEGF 165 but not VEGF189. Proc Nad Acad Sci USA 1997; 94(22):12081–12087.CrossRefGoogle Scholar
  42. 42.
    Grunstein J, Masbad JJ, Hickey R et al. Isoforms of vascular endothelial growth factor act in a coordinate fashion To recruit and expand tumor vasculature. Mol Cell Biol 2000; 20(19):7282–7291.PubMedCrossRefGoogle Scholar
  43. 43.
    Ruhrberg C, Gerhardt H, Golding M et al. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev 2002; 16(20):2684–2698.PubMedCrossRefGoogle Scholar
  44. 44.
    Ng YS, D’Amore PA. Therapeutic angiogenesis for cardiovascular disease. Curr Control Trials Cardiovasc Med 2001; 2(6):278–285.PubMedCrossRefGoogle Scholar
  45. 45.
    Brinkman BM. Splice variants as cancer biomarkers. Clin Biochem 2004; 37(7):584–594.PubMedCrossRefGoogle Scholar
  46. 46.
    Ishida S, Usui T, Yamashiro K et al. VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J Exp Med 2003; 198(3):483–489.PubMedCrossRefGoogle Scholar
  47. 47.
    Jain RK. Molecular regulation of vessel maturation. Nat Med 2003; 9(6):685–693.PubMedCrossRefGoogle Scholar
  48. 48.
    Nakamura M, Abe Y, Tokunaga T. Pathological significance of vascular endothelial growth factor A isoform expression in human cancer. Pathol Int 2002; 52(5–6):331–339.PubMedCrossRefGoogle Scholar
  49. 49.
    Lange T, Guttmann-Raviv N, Baruch L et al. VEGF162, a new heparin-binding vascular endothelial growth factor splice form that is expressed in transformed human cells. J Biol Chem 2003; 278(19):17164–17169.PubMedCrossRefGoogle Scholar
  50. 50.
    Woolard J, Wang WY, Bevan HS et al. VEGFl65b, an inhibitory vascular endothelial growth factor splice variant: Mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res 2004; 64(21):7822–7835.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

  • Yin-Shan Ng
    • 1
  1. 1.(OSI) EyetechLexingtonUSA

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