Modulatory Role of VEGF in Angiogenesis for Cell Survival

  • Dipti Gatne
  • Veeranjaneyulu Addepalli
  • Dev D. Santani
Part of the Advances in Biochemistry in Health and Disease book series (ABHD, volume 4)


Vascular endothelial growth factor (VEGF) is established to play a crucial role in angiogenesis, cell survival, and thus appear to be important in many pathophysiological processes. VEGF and anti VEGF therapy have been used in treatment of cancer, diabetic retinopathy, cardiovascular disorders, psoriasis, wound healing, age-related macular degeneration, and so on. This review elaborates role of VEGF as cell survival factor in various diseases and several therapeutic strategies involving VEGFs and their receptors. The development of side effects and resistance to therapy involving VEGF needs to be considered while designing new molecules along with molecular modeling techniques.


VEGF  Angiogenesis Cancer Cell survival 



We express our gratitude to Department of Biotechnology (DBT), Government of India for providing financial support and SPP School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, India for providing facilities to carry out the research work.


  1. 1.
    Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438:967–974PubMedCrossRefGoogle Scholar
  2. 2.
    Pandya NM, Dhalla NS, Santani DD (2006) Angiogenesis—a new target for future therapy. Vasc Pharmacol 44:265–274CrossRefGoogle Scholar
  3. 3.
    Sato Y (2000) Molecular mechanism of angiogenesis transcription factors and their therapeutic relevance. Pharmacol Ther 87:51–60PubMedCrossRefGoogle Scholar
  4. 4.
    Otrock ZK, Mahfouz RA, Makarem JA, Shamseddine AI (2007) Understanding the biology of angiogenesis: review of the most important molecular mechanisms. Blood Cells Mol Dis 39:212–220PubMedCrossRefGoogle Scholar
  5. 5.
    Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8:579–591PubMedCrossRefGoogle Scholar
  6. 6.
    Liekens S, Clercq ED, Neyts J (2001) Angiogenesis: regulators and clinical applications. Biochem Pharmacol 61:253–270PubMedCrossRefGoogle Scholar
  7. 7.
    Suk HB, Sung CL, Soo HC et al (2010) Vascular endothelial growth factor as an autocrine survival factor for retinal pigment epithelial cells under oxidative stress via the VEGF-R2/PI3 K/Akt. Invest Ophthalmol Vis Sci 51:1190–1197CrossRefGoogle Scholar
  8. 8.
    Brusselmans K, Bono F, Collen D et al (2005) A novel role for vascular endothelial growth factor as an autocrine survival factor for embryonic stem cells during hypoxia. J Biol Chem 280:3493–3499PubMedCrossRefGoogle Scholar
  9. 9.
    Wada T, Haigh JJ, Ema M et al (2006) Vascular endothelial growth factor directly inhibits primitive neural stem cell survival but promotes definitive neural stem cell survival. J Neurosci 26:6803–6812PubMedCrossRefGoogle Scholar
  10. 10.
    Moreira IS, Fernandes PA, Ramos MJ (2007) Vascular endothelial growth factor (VEGF) inhibition—a critical review. Anti-Cancer Agents Med Chem 7:223–245CrossRefGoogle Scholar
  11. 11.
    Ferrari G, Pintucci G, Seghezzi G et al (2006) VEGF, a prosurvival factor, acts in concert with TGF-1 to induce endothelial cell apoptosis. Proc Natl Acad Sci USA 103:17260–17265PubMedCrossRefGoogle Scholar
  12. 12.
    Kowanetz M, Ferrara N (2006) Vascular endothelial growth factor signalling pathways: therapeutic perspective. Clin Cancer Res 12:5018–5022PubMedCrossRefGoogle Scholar
  13. 13.
    Tae-Hee L, Seyha S, Masayuki S et al (2007) Vascular endothelial growth factor mediates intracrine survival in human breast carcinoma cells through internally expressed VEGFR1/FLT1. PLoS Med 4:e186. doi: 10.1371/journal.pmed.0040186 CrossRefGoogle Scholar
  14. 14.
    Soltau J, Drevs J (2009) Mode of action and clinical impact of VEGF signalling inhibitors. Expert Rev Anticancer Ther 9:649–662PubMedCrossRefGoogle Scholar
  15. 15.
    Rahimi N (2006) VEGFR-1 and VEGFR-2: two non-identical twins with a unique physiognomy. Front Biosci 11:818–829PubMedCrossRefGoogle Scholar
  16. 16.
    Matsumoto T, Bohman S, Dixelius J et al (2005) VEGF receptor-2 Y951 signalling and a role for the adapter molecule TSAd in tumor angiogenesis. EMBO J 24:2342–2353PubMedCrossRefGoogle Scholar
  17. 17.
    Laakkonen P, Waltari M, Holopainen T et al (2007) Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res 67:593–599PubMedCrossRefGoogle Scholar
  18. 18.
    Rosen LS (2005) VEGF-targeted therapy: therapeutic potential and recent advances. Oncologist 10:382–391PubMedCrossRefGoogle Scholar
  19. 19.
    Sun S, Schiller JH (2007) Angiogenesis inhibitors in the treatment of lung cancer. Crit Rev Oncol Hematol 62:93–104PubMedCrossRefGoogle Scholar
  20. 20.
    Carpini JD, Karam AK, Montgomery L (2010) Vascular endothelial growth factor and its relationship to the prognosis and treatment of breast, ovarian, and cervical cancer. Angiogenesis 13:43–58PubMedCrossRefGoogle Scholar
  21. 21.
    Dong X, Han ZC, Yang R (2007) Angiogenesis and antiangiogenic therapy in hematologic malignancies. Crit Rev Oncol Hematol 62:105–118PubMedCrossRefGoogle Scholar
  22. 22.
    Burris H, Rocha-Lima C (2008) New therapeutic directions for advanced pancreatic cancer: targeting the epidermal growth factor and vascular endothelial growth factor pathways. Oncologist 13:289–298PubMedCrossRefGoogle Scholar
  23. 23.
    Winkler F, Kozin SV, Tong RT et al (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553–563PubMedGoogle Scholar
  24. 24.
    Yoon-Jin L, Maduekwe UN et al (2010) Differential effects of VEGFR-1 and VEGFR-2 inhibition on tumor metastases based on host organ environment. Cancer Res 70:8357–8367CrossRefGoogle Scholar
  25. 25.
    Tomanek RJ, Sandra A, Zheng W et al (2001) Vascular endothelial growth factor and basic fibroblast growth factor differentially modulate early postnatal coronary angiogenesis. Circ Res 88:1135–1141PubMedCrossRefGoogle Scholar
  26. 26.
    Zentilin L, Puligadda U, Lionetti V et al (2010) Cardiomyocyte VEGFR-1 activation by VEGF-B induces compensatory hypertrophy and preserves cardiac function after myocardial infarction. FASEB J 24:1467–1478PubMedCrossRefGoogle Scholar
  27. 27.
    Crawford TN, Alfaro DV, Kerrison JB, Jablon EP (2009) Diabetic retinopathy and angiogenesis. Curr Diabetes Rev 5:8–13PubMedCrossRefGoogle Scholar
  28. 28.
    Noe A, Jost M, Lambert V, Lecomte J, Jean-Marie R (2007) Anti-angiogenic therapy of exudative age-related macular degeneration: current progress and emerging concepts. Trends Mol Med 13:345–352CrossRefGoogle Scholar
  29. 29.
    Ng EWM, Adamis AP (2005) Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration. Can J Ophthalmol 40:352–368PubMedGoogle Scholar
  30. 30.
    Paleolog EM (2002) Angiogenesis in rheumatoid arthritis. Arthritis Res 4:S81–S90PubMedCrossRefGoogle Scholar
  31. 31.
    Ashraf S, Walsh DA (2008) Angiogenesis in osteoarthritis. Curr Opin Rheumatol 20:573–580PubMedCrossRefGoogle Scholar
  32. 32.
    Lambert C, Mathy-Hartert M, Jean-Emile D et al (2012) Characterization of synovial angiogenesis in osteoarthritis patients and its modulation by chondroitin sulphate. Arthritis Res Ther 14:R58PubMedCrossRefGoogle Scholar
  33. 33.
    Azfara RS, Gelfand JM (2008) Psoriasis and metabolic disease: epidemiology and pathophysiology. Curr Opin Rheumatol 20:416–422CrossRefGoogle Scholar
  34. 34.
    Goedkoop AY, Kraan MC, Picavet DI et al (2004) Deactivation of endothelium and reduction in angiogenesis in psoriatic skin and synovium by low dose infliximab therapy in combination with stable methotrexate therapy: a prospective single-centre study. Arthritis Res Ther 6:R326–R334PubMedCrossRefGoogle Scholar
  35. 35.
    Lafuente JV, Argandon EG, Mitre B (2006) VEGFR-2 expression in brain injury: its distribution related to brain–blood barrier markers. J Neural Transm 113:487–496PubMedCrossRefGoogle Scholar
  36. 36.
    Munaut C, Lorquet S, Pequeux C et al (2012) Differential expression of VEGFR-2 and its soluble form in preeclampsia. PLoS One 7:e33475. doi: 10.1371/journal.pone.0033475 PubMedCrossRefGoogle Scholar
  37. 37.
    Tortora G, Melisi D, Ciardiello F (2004) Angiogenesis: a target for cancer therapy. Curr Pharm Des 10:11–26PubMedCrossRefGoogle Scholar
  38. 38.
    Borgstrom P, Hillan KJ, Sriramarao P, Ferrara N (1996) Complete inhibition of angiogenesis and growth of microtumors by anti-vascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital videomicroscopy. Cancer Res 56:4032–4039PubMedGoogle Scholar
  39. 39.
    Gotink KJ, Verheul HMW (2010) Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis 13:1–14PubMedCrossRefGoogle Scholar
  40. 40.
    Soria JC, Fayette J, Armand JP (2004) Molecular targeting: targeting angiogenesis in solid tumors. Ann Oncol 15:iv223–iv227PubMedCrossRefGoogle Scholar
  41. 41.
    Schenone S, Bondavalli F, Botta M (2007) Antiangiogenic agents: an update on small molecule VEGFR inhibitors. Curr Med Chem 14:2495–2516PubMedCrossRefGoogle Scholar
  42. 42.
    Bjorndahl M, Cao R, Eriksson A, Cao Y (2004) Blockage of VEGF-induced angiogenesis by preventing VEGF secretion. Circ Res 94:1443–1450PubMedCrossRefGoogle Scholar
  43. 43.
    Udugamasooriya DG, Ritchie C, Brekken RA, Kodadek T (2008) A peptoid antagonist of VEGF receptor 2 recognizes a ‘hotspot’ in the extracellular domain distinct from the hormone-binding site. Bioorg Med Chem 16:6338–6343PubMedCrossRefGoogle Scholar
  44. 44.
    Udugamasooriya DG, Dunham G, Ritchie C, Rolf A, Brekken b, Kodadek T (2008) The pharmacophore of a peptoid VEGF receptor 2 antagonist includes both side chain and main chain residues. Bioorg Med Chem Lett 18:5892–5894PubMedCrossRefGoogle Scholar
  45. 45.
    Liu Y, Gray NS (2006) Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2:358–364PubMedCrossRefGoogle Scholar
  46. 46.
    Bozec A, Formento P, Lassalle S et al (2007) Dual inhibition of EGFR and VEGFR pathways in combination with irradiation: antitumour supra-additive effects on human head and neck cancer xenografts. Br J Cancer 97:65–72PubMedCrossRefGoogle Scholar
  47. 47.
    Larsen AK, Ouaret D, Ouadrani KE, Petitprez A (2011) Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis. Pharmacol Ther 131:80–90PubMedCrossRefGoogle Scholar
  48. 48.
    Sumariwalla PF, Cao Y, Hua-Lin W, Feldmann M, Paleolog EM (2003) The angiogenesis inhibitor protease-activated kringles 1–5 reduces the severity of murine collagen-induced arthritis. Arthritis Res Ther 5:R32–R39PubMedCrossRefGoogle Scholar
  49. 49.
    Roberts N, Kloos B, Cassella M et al (2006) Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res 66:2650–2657PubMedCrossRefGoogle Scholar
  50. 50.
    Medhane D, Ghone S, Mohanraj K, Addepalli V (2010) Conference on chemical biology for drug discovery: perspective and challenges, organized by indian society of chemist and biologist (ISCB) at central drug research institute, Lucknow, India. Part of findings of our work in area of angiogenesis inhibitors was presented in this conferenceGoogle Scholar
  51. 51.
    Neaz MM, Pasha FA, Muddassar M et al (2008) Pharmacophore based 3D-QSAR study of VEGFR-2 inhibitors. Med Chem Res 18:127–142CrossRefGoogle Scholar
  52. 52.
    Lei Y, Haider HK, Shujia J, Sim ESK (2004) Therapeutic angiogenesis: devising new strategies based on past experiences. Basic Res Cardiol 99:121–132PubMedCrossRefGoogle Scholar
  53. 53.
    Eskens F, Verweij J (2006) The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors. Rev Eur J Cancer 42:3127–3139CrossRefGoogle Scholar
  54. 54.
    Crawford Y, Ferrara N (2009) Tumor and stromal pathways mediating refractoriness/resistance to anti-angiogenic therapies. Trends Pharmacol Sci 30:624–630PubMedCrossRefGoogle Scholar
  55. 55.
    Ellis LM, Hicklin DJ (2008) Pathways Mediating Resistance to Vascular Endothelial Growth Factor Targeted Therapy. Clin Cancer Res 14:6371–6375PubMedCrossRefGoogle Scholar
  56. 56.
    Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signalling in late-stage pancreatic islet tumors. Cancer Cell 8:299–309PubMedCrossRefGoogle Scholar
  57. 57.
    Hoeben A, Landuyt B, Highley MS et al (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56:549–580PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Dipti Gatne
    • 1
  • Veeranjaneyulu Addepalli
    • 2
  • Dev D. Santani
    • 3
  1. 1.Department of Pharmaceutical ChemistrySPP School of Pharmacy and Technology Management, SVKM’s NMIMSMumbaiIndia
  2. 2.Department of PharmacologySPP School of Pharmacy & Technology Management, SVKM’s NMIMSMumbaiIndia
  3. 3.Department of PharmacologyL.M. College of PharmacyAhmedabadIndia

Personalised recommendations