Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond

Abstract

Despite the enormous progress made in terms of prevention and early intervention, a pressing need remains to develop innovative therapeutic strategies for ischemic cardiovascular disorders, including acute myocardial infarction, chronic cardiac ischemia, peripheral artery disease and stroke. The induction of new blood vessel formation by delivering angiogenic genes to ischemic tissues continues to appear as a promising, alternative strategy to currently available therapies. In aspiring to induce therapeutic angiogenesis, the members of the vascular endothelial growth factor (VEGF) family have long been recognized as major molecular tools. Remarkably, VEGF family members have recently been recognized to also exert multiple, non-angiogenic effects on various cell types, including neurons, skeletal muscle and cardiac cells. Here, we critically review the VEGF-based therapies that have already reached clinical experimentation and highlight the pleiotropic activities of VEGF factors that might create new opportunities for therapeutic application.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Ferrara N . VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2002; 2: 795–803.

    Article  CAS  PubMed  Google Scholar 

  2. Ide AG, Baker NH, Warren SL . Vascularization of the Brown–Pearce rabbit epithelioma transplant as seen in the transparent ear chamber. Am J Roentgenol 1939; 42: 891–899.

    Google Scholar 

  3. Folkman J, Merler E, Abernathy C, Williams G . Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971; 133: 275–288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF . Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983; 219: 983–985.

    Article  CAS  PubMed  Google Scholar 

  5. 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: 851–858.

    Article  CAS  PubMed  Google Scholar 

  6. Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D et al. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 2003; 9: 936–943.

    Article  CAS  PubMed  Google Scholar 

  7. Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D et al. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 1992; 187: 1579–1586.

    Article  CAS  PubMed  Google Scholar 

  8. Fujisawa H, Kitsukawa T . Receptors for collapsin/semaphorins. Curr Opin Neurobiol 1998; 8: 587–592.

    Article  CAS  PubMed  Google Scholar 

  9. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M . Neuropilin-1 is expressed by endothelial and tumor cells as an isoform- specific receptor for vascular endothelial growth factor. Cell 1998; 92: 735–745.

    Article  CAS  PubMed  Google Scholar 

  10. Carmeliet P, Jain RK . Molecular mechanisms and clinical applications of angiogenesis. Nature 2011; 473: 298–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Potente M, Gerhardt H, Carmeliet P . Basic and therapeutic aspects of angiogenesis. Cell 2011; 146: 873–887.

    Article  CAS  PubMed  Google Scholar 

  12. Adams RH, Alitalo K . Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 2007; 8: 464–478.

    Article  CAS  PubMed  Google Scholar 

  13. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L . VEGF receptor signalling—in control of vascular function. Nat Rev Mol Cell Biol 2006; 7: 359–371.

    Article  CAS  PubMed  Google Scholar 

  14. Giacca M . Non-redundant functions of the protein isoforms arising from alternative splicing of the VEGF-A pre-mRNA. Transcription 2010; 1: 149–153.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Rissanen TT, Yla-Herttuala S . Current status of cardiovascular gene therapy. Mol Ther 2007; 15: 1233–1247.

    Article  CAS  PubMed  Google Scholar 

  16. Henry TD, Annex BH, McKendall GR, Azrin MA, Lopez JJ, Giordano FJ et al. The VIVA trial: vascular endothelial growth factor in ischemia for vascular angiogenesis. Circulation 2003; 107: 1359–1365.

    Article  CAS  PubMed  Google Scholar 

  17. Sato K, Laham RJ, Pearlman JD, Novicki D, Sellke FW, Simons M et al. Efficacy of intracoronary versus intravenous FGF-2 in a pig model of chronic myocardial ischemia. Ann Thorac Surg 2000; 70: 2113–2118.

    Article  CAS  PubMed  Google Scholar 

  18. Isner JM . Vascular endothelial growth factor: gene therapy and therapeutic angiogenesis. Am J Cardiol 1998; 82: 63S–64S.

    Article  CAS  PubMed  Google Scholar 

  19. Isner JM, Pieczek A, Schainfeld R, Blair R, Haley L, Asahara T et al. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb. Lancet 1996; 348: 370–374.

    Article  CAS  PubMed  Google Scholar 

  20. Baumgartner I, Pieczek A, Manor O, Blair R, Kearney M, Walsh K et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 1998; 97: 1114–1123.

    Article  CAS  PubMed  Google Scholar 

  21. Kim HJ, Jang SY, Park JI, Byun J, Kim DI, Do YS et al. Vascular endothelial growth factor-induced angiogenic gene therapy in patients with peripheral artery disease. Exp Mol Med 2004; 36: 336–344.

    Article  CAS  PubMed  Google Scholar 

  22. Baumgartner I, Rauh G, Pieczek A, Wuensch D, Magner M, Kearney M et al. Lower-extremity edema associated with gene transfer of naked DNA encoding vascular endothelial growth factor. Ann Intern Med 2000; 132: 880–884.

    Article  CAS  PubMed  Google Scholar 

  23. Losordo DW, Vale PR, Symes JF, Dunnington CH, Esakof DD, Maysky M et al. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation 1998; 98: 2800–2804.

    Article  CAS  PubMed  Google Scholar 

  24. Symes JF, Losordo DW, Vale PR, Lathi KG, Esakof DD, Mayskiy M et al. Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease. Ann Thorac Surg 1999; 68: 830–836; discussion 836–837.

    Article  CAS  PubMed  Google Scholar 

  25. Fortuin FD, Vale P, Losordo DW, Symes J, DeLaria GA, Tyner JJ et al. One-year follow-up of direct myocardial gene transfer of vascular endothelial growth factor-2 using naked plasmid deoxyribonucleic acid by way of thoracotomy in no-option patients. Am J Cardiol 2003; 92: 436–439.

    Article  CAS  PubMed  Google Scholar 

  26. Reilly JP, Grise MA, Fortuin FD, Vale PR, Schaer GL, Lopez J et al. Long-term (2-year) clinical events following transthoracic intramyocardial gene transfer of VEGF-2 in no-option patients. J Interv Cardiol 2005; 18: 27–31.

    Article  PubMed  Google Scholar 

  27. Vale PR, Losordo DW, Milliken CE, Maysky M, Esakof DD, Symes JF et al. Left ventricular electromechanical mapping to assess efficacy of phVEGF (165) gene transfer for therapeutic angiogenesis in chronic myocardial ischemia. Circulation 2000; 102: 965–974.

    Article  CAS  PubMed  Google Scholar 

  28. Sarkar N, Ruck A, Kallner G, Y-Hassan S, Blomberg P, Islam KB et al. Effects of intramyocardial injection of phVEGF-A165 as sole therapy in patients with refractory coronary artery disease—12-month follow-up: angiogenic gene therapy. J Intern Med 2001; 250: 373–381.

    Article  CAS  PubMed  Google Scholar 

  29. Losordo DW, Vale PR, Hendel RC, Milliken CE, Fortuin FD, Cummings N et al. Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation 2002; 105: 2012–2018.

    Article  CAS  PubMed  Google Scholar 

  30. Mendiz O, Favaloro L, Diez M, Valdivieso L, Bercovich A, Criscuolo M et al. Abstract 15 235: high-dose plasmid VEGF gene transfer in patients with severe coronary artery disease: final results of the first Latin American trial of gene therapy in myocardial ischemia. Circulation 2011; 124 (Suppl.): A15235.

    Google Scholar 

  31. Gyongyosi M, Khorsand A, Zamini S, Sperker W, Strehblow C, Kastrup J et al. NOGA-guided analysis of regional myocardial perfusion abnormalities treated with intramyocardial injections of plasmid encoding vascular endothelial growth factor A-165 in patients with chronic myocardial ischemia: subanalysis of the EUROINJECT-ONE multicenter double-blind randomized study. Circulation 2005; 112 (Suppl): I157–I165.

    PubMed  Google Scholar 

  32. Kastrup J, Jorgensen E, Ruck A, Tagil K, Glogar D, Ruzyllo W et al. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris. A randomized double-blind placebo-controlled study: the Euroinject One Trial. J Am Coll Cardiol 2005; 45: 982–988.

    Article  CAS  PubMed  Google Scholar 

  33. Stewart DJ, Kutryk MJ, Fitchett D, Freeman M, Camack N, Su Y et al. VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: results of the NORTHERN trial. Mol Ther 2009; 17: 1109–1115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ripa RS, Wang Y, Jorgensen E, Johnsen HE, Hesse B, Kastrup J . Intramyocardial injection of vascular endothelial growth factor-A165 plasmid followed by granulocyte-colony stimulating factor to induce angiogenesis in patients with severe chronic ischaemic heart disease. Eur Heart J 2006; 27: 1785–1792.

    Article  CAS  PubMed  Google Scholar 

  35. Kukula K, Chojnowska L, Dabrowski M, Witkowski A, Chmielak Z, Skwarek M et al. Intramyocardial plasmid-encoding human vascular endothelial growth factor A165/basic fibroblast growth factor therapy using percutaneous transcatheter approach in patients with refractory coronary artery disease (VIF-CAD). Am Heart J 2011; 161: 581–589.

    Article  CAS  PubMed  Google Scholar 

  36. Kusumanto YH, van Weel V, Mulder NH, Smit AJ, van den Dungen JJ, Hooymans JM et al. Treatment with intramuscular vascular endothelial growth factor gene compared with placebo for patients with diabetes mellitus and critical limb ischemia: a double-blind randomized trial. Hum Gene Ther 2006; 17: 683–691.

    Article  CAS  PubMed  Google Scholar 

  37. Liu PQ, Rebar EJ, Zhang L, Liu Q, Jamieson AC, Liang Y et al. Regulation of an endogenous locus using a panel of designed zinc finger proteins targeted to accessible chromatin regions. Activation of vascular endothelial growth factor A. J Biol Chem 2001; 276: 11323–11334.

    Article  CAS  PubMed  Google Scholar 

  38. Rebar EJ, Huang Y, Hickey R, Nath AK, Meoli D, Nath S et al. Induction of angiogenesis in a mouse model using engineered transcription factors. Nat Med 2002; 8: 1427–1432.

    Article  CAS  PubMed  Google Scholar 

  39. Dai Q, Huang J, Klitzman B, Dong C, Goldschmidt-Clermont PJ, March KL et al. Engineered zinc finger-activating vascular endothelial growth factor transcription factor plasmid DNA induces therapeutic angiogenesis in rabbits with hindlimb ischemia. Circulation 2004; 110: 2467–2475.

    Article  CAS  PubMed  Google Scholar 

  40. Yu J, Lei L, Liang Y, Hinh L, Hickey RP, Huang Y et al. An engineered VEGF-activating zinc finger protein transcription factor improves blood flow and limb salvage in advanced-age mice. FASEB J 2006; 20: 479–481.

    Article  CAS  PubMed  Google Scholar 

  41. Tafuro S, Ayuso E, Zacchigna S, Zentilin L, Moimas S, Dore F et al. Inducible adeno-associated virus vectors promote functional angiogenesis in adult organisms via regulated vascular endothelial growth factor expression. Cardiovasc Res 2009; 83: 663–671.

    Article  CAS  PubMed  Google Scholar 

  42. Belch J, Hiatt WR, Baumgartner I, Driver IV, Nikol S, Norgren L et al. Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia. Lancet 2011; 377: 1929–1937.

    Article  CAS  PubMed  Google Scholar 

  43. Rajagopalan S, Shah M, Luciano A, Crystal R, Nabel EG . Adenovirus-mediated gene transfer of VEGF (121) improves lower-extremity endothelial function and flow reserve. Circulation 2001; 104: 753–755.

    Article  CAS  PubMed  Google Scholar 

  44. Rajagopalan S, Trachtenberg J, Mohler E, Olin J, McBride S, Pak R et al. Phase I study of direct administration of a replication deficient adenovirus vector containing the vascular endothelial growth factor cDNA (CI-1023) to patients with claudication. Am J Cardiol 2002; 90: 512–516.

    Article  CAS  PubMed  Google Scholar 

  45. Rajagopalan S, Mohler III E, Lederman RJ, Saucedo J, Mendelsohn FO, Olin J et al. Regional angiogenesis with vascular endothelial growth factor (VEGF) in peripheral arterial disease: design of the RAVE trial. Am Heart J 2003; 145: 1114–1118.

    Article  CAS  PubMed  Google Scholar 

  46. Rajagopalan S, Mohler III ER, Lederman RJ, Mendelsohn FO, Saucedo JF, Goldman CK et al. Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication. Circulation 2003; 108: 1933–1938.

    Article  CAS  PubMed  Google Scholar 

  47. Rosengart TK, Lee LY, Patel SR, Sanborn TA, Parikh M, Bergman GW et al. Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. Circulation 1999; 100: 468–474.

    Article  CAS  PubMed  Google Scholar 

  48. Stewart DJ, Hilton JD, Arnold JM, Gregoire J, Rivard A, Archer SL et al. Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF (121) (AdVEGF121) versus maximum medical treatment. Gene Therapy 2006; 13: 1503–1511.

    Article  CAS  PubMed  Google Scholar 

  49. Fuchs S, Dib N, Cohen BM, Okubagzi P, Diethrich EB, Campbell A et al. A randomized, double-blind, placebo-controlled, multicenter, pilot study of the safety and feasibility of catheter-based intramyocardial injection of AdVEGF121 in patients with refractory advanced coronary artery disease. Catheter Cardiovasc Interv 2006; 68: 372–378.

    Article  PubMed  Google Scholar 

  50. Kastrup J, Jorgensen E, Fuchs S, Nikol S, Botker HE, Gyongyosi M et al. A randomised, double-blind, placebo-controlled, multicentre study of the safety and efficacy of BIOBYPASS (AdGVVEGF121.10NH) gene therapy in patients with refractory advanced coronary artery disease: the NOVA trial. EuroIntervention 2011; 6: 813–818.

    Article  PubMed  Google Scholar 

  51. Makinen K, Manninen H, Hedman M, Matsi P, Mussalo H, Alhava E 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 2002; 6: 127–133.

    Article  CAS  PubMed  Google Scholar 

  52. Hedman M, Hartikainen J, Syvanne M, Stjernvall J, Hedman A, Kivela A et al. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT). Circulation 2003; 107: 2677–2683.

    Article  CAS  PubMed  Google Scholar 

  53. Hedman M, Muona K, Hedman A, Kivela A, Syvanne M, Eranen J et al. Eight-year safety follow-up of coronary artery disease patients after local intracoronary VEGF gene transfer. Gene Therapy 2009; 16: 629–634.

    Article  CAS  PubMed  Google Scholar 

  54. Muona K, Makinen K, Hedman M, Manninen H, Yla-Herttuala S . 10-year safety follow-up in patients with local VEGF gene transfer to ischemic lower limb. Gene Therapy 2011; e-pub ahead of print 21 July 2011; doi:10.1038/gt.2011.109.

  55. Rutanen J, Rissanen TT, Markkanen JE, Gruchala M, Silvennoinen P, Kivela A et al. Adenoviral catheter-mediated intramyocardial gene transfer using the mature form of vascular endothelial growth factor-D induces transmural angiogenesis in porcine heart. Circulation 2004; 109: 1029–1035.

    Article  CAS  PubMed  Google Scholar 

  56. Fuster V, Charlton P, Boyd A . Clinical protocol. A phase IIb, randomized, multicenter, double-blind study of the efficacy and safety of Trinam (EG004) in stenosis prevention at the graft–vein anastomosis site in dialysis patients. Hum Gene Ther 2001; 12: 2025–2027.

    CAS  PubMed  Google Scholar 

  57. Gilgenkrantz H, Duboc D, Juillard V, Couton D, Pavirani A, Guillet JG et al. Transient expression of genes transferred in vivo into heart using first-generation adenoviral vectors: role of the immune response. Hum Gene Ther 1995; 6: 1265–1274.

    Article  CAS  PubMed  Google Scholar 

  58. Daya S, Berns KI . Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev 2008; 21: 583–593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mingozzi F, High KA . Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Nat Rev Genet 2011; 12: 341–355.

    Article  CAS  PubMed  Google Scholar 

  60. Arsic N, Zentilin L, Zacchigna S, Santoro D, Stanta G, Salvi S et al. Induction of functional neovascularization by combined VEGF and angiopoietin-1 gene transfer using AAV vectors. Mol Ther 2003; 7: 450–459.

    Article  CAS  PubMed  Google Scholar 

  61. Cervelli T, Palacios JA, Zentilin L, Mano M, Schwartz RA, Weitzman MD et al. Processing of recombinant AAV genomes occurs in specific nuclear structures that overlap with foci of DNA-damage-response proteins. J Cell Sci 2008; 121 (Part 3): 349–357.

    Article  CAS  PubMed  Google Scholar 

  62. Gerber HP, Malik AK, Solar GP, Sherman D, Liang XH, Meng G et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 2002; 417: 954–958.

    Article  CAS  PubMed  Google Scholar 

  63. Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 2002; 8: 831–840.

    Article  CAS  PubMed  Google Scholar 

  64. Perelman N, Selvaraj SK, Batra S, Luck LR, Erdreich-Epstein A, Coates TD et al. Placenta growth factor activates monocytes and correlates with sickle cell disease severity. Blood 2003; 102: 1506–1514.

    Article  CAS  PubMed  Google Scholar 

  65. Oe H, Kaido T, Mori A, Onodera H, Imamura M . Hepatocyte growth factor as well as vascular endothelial growth factor gene induction effectively promotes liver regeneration after hepatectomy in Solt–Farber rats. Hepatogastroenterology 2005; 52: 1393–1397.

    CAS  PubMed  Google Scholar 

  66. Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N . VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 1999; 5: 623–628.

    Article  CAS  PubMed  Google Scholar 

  67. Maes C, Carmeliet P, Moermans K, Stockmans I, Smets N, Collen D et al. Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech Dev 2002; 111: 61–73.

    Article  CAS  PubMed  Google Scholar 

  68. Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 2003; 111: 707–716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003; 111: 649–658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zacchigna S, Lambrechts D, Carmeliet P . Neurovascular signalling defects in neurodegeneration. Nat Rev Neurosci 2008; 9: 169–181.

    Article  CAS  PubMed  Google Scholar 

  71. Sondell M, Sundler F, Kanje M . Vascular endothelial growth factor is a neurotrophic factor which stimulates axonal outgrowth through the flk-1 receptor. Eur J Neurosci 2000; 12: 4243–4254.

    Article  CAS  PubMed  Google Scholar 

  72. Jin KL, Mao XO, Greenberg DA . Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia. Proc Natl Acad Sci USA 2000; 97: 10242–10247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Silverman WF, Krum JM, Mani N, Rosenstein JM . Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures. Neuroscience 1999; 90: 1529–1541.

    Article  CAS  PubMed  Google Scholar 

  74. Storkebaum E, Lambrechts D, Dewerchin M, Moreno-Murciano MP, Appelmans S, Oh H et al. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nat Neurosci 2005; 8: 85–92.

    Article  CAS  PubMed  Google Scholar 

  75. Schratzberger P, Walter DH, Rittig K, Bahlmann FH, Pola R, Curry C et al. Reversal of experimental diabetic neuropathy by VEGF gene transfer. J Clin Invest 2001; 107: 1083–1092.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Isner JM, Ropper A, Hirst K . VEGF gene transfer for diabetic neuropathy. Hum Gene Ther 2001; 12: 1593–1594.

    CAS  PubMed  Google Scholar 

  77. Ropper AH, Gorson KC, Gooch CL, Weinberg DH, Pieczek A, Ware JH et al. Vascular endothelial growth factor gene transfer for diabetic polyneuropathy: a randomized, double-blinded trial. Ann Neurol 2009; 65: 386–393.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Lambrechts D, Carmeliet P . VEGF at the neurovascular interface: therapeutic implications for motor neuron disease. Biochim Biophys Acta 2006; 1762: 1109–1121.

    Article  CAS  PubMed  Google Scholar 

  79. Ishida A, Murray J, Saito Y, Kanthou C, Benzakour O, Shibuya M et al. Expression of vascular endothelial growth factor receptors in smooth muscle cells. J Cell Physiol 2001; 188: 359–368.

    Article  CAS  PubMed  Google Scholar 

  80. Storkebaum E, Ruiz de Almodovar C, Meens M, Zacchigna S, Mazzone M, Vanhoutte G et al. Impaired autonomic regulation of resistance arteries in mice with low vascular endothelial growth factor or upon vascular endothelial growth factor trap delivery. Circulation 2010; 122: 273–281.

    Article  CAS  PubMed  Google Scholar 

  81. Arsic N, Zacchigna S, Zentilin L, Ramirez-Correa G, Pattarini L, Salvi A et al. Vascular endothelial growth factor stimulates skeletal muscle regeneration in vivo. Mol Ther 2004; 10: 844–854.

    Article  CAS  PubMed  Google Scholar 

  82. Messina S, Mazzeo A, Bitto A, Aguennouz M, Migliorato A, De Pasquale MG et al. VEGF overexpression via adeno-associated virus gene transfer promotes skeletal muscle regeneration and enhances muscle function in mdx mice. FASEB J 2007; 21: 3737–3746.

    Article  CAS  PubMed  Google Scholar 

  83. Azambuja AP, Portillo-Sanchez V, Rodrigues MV, Omae SV, Schechtman D, Strauss BE et al. Retinoic acid and VEGF delay smooth muscle relative to endothelial differentiation to coordinate inner and outer coronary vessel wall morphogenesis. Circ Res 2010; 107: 204–216.

    Article  CAS  PubMed  Google Scholar 

  84. Ferrarini M, Arsic N, Recchia FA, Zentilin L, Zacchigna S, Xu X et al. Adeno-associated virus-mediated transduction of VEGF165 improves cardiac tissue viability and functional recovery after permanent coronary occlusion in conscious dogs. Circ Res 2006; 98: 954–961.

    Article  CAS  PubMed  Google Scholar 

  85. Pepe M, Mamdani M, Zentilin L, Csiszar A, Qanud K, Zacchigna S et al. Intramyocardial VEGF-B167 gene delivery delays the progression towards congestive failure in dogs with pacing-induced dilated cardiomyopathy. Circ Res 2010; 106: 1893–1903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zentilin L, Puligadda U, Lionetti V, Zacchigna S, Collesi C, Pattarini L et al. Cardiomyocyte VEGFR-1 activation by VEGF-B induces compensatory hypertrophy and preserves cardiac function after myocardial infarction. FASEB J 2009; 24: 1467–1478.

    Article  CAS  PubMed  Google Scholar 

  87. Zacchigna S, Pattarini L, Zentilin L, Moimas S, Carrer A, Sinigaglia M et al. Bone marrow cells recruited through the neuropilin-1 receptor promote arterial formation at the sites of adult neoangiogenesis. J Clin Invest 2008; 118: 2062–2075.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Bry M, Kivela R, Holopainen T, Anisimov A, Tammela T, Soronen J et al. Vascular endothelial growth factor-B acts as a coronary growth factor in transgenic rats without inducing angiogenesis, vascular leak, or inflammation. Circulation 2010; 122: 1725–1733.

    Article  CAS  PubMed  Google Scholar 

  89. Levy AP, Levy NS, Loscalzo J, Calderone A, Takahashi N, Yeo KT et al. Regulation of vascular endothelial growth factor in cardiac myocytes. Circ Res 1995; 76: 758–766.

    Article  CAS  PubMed  Google Scholar 

  90. Xu XH, Xu J, Xue L, Cao HL, Liu X, Chen YJ . VEGF attenuates development from cardiac hypertrophy to heart failure after aortic stenosis through mitochondrial mediated apoptosis and cardiomyocyte proliferation. J Cardiothorac Surg 2011; 6: 54.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Rottbauer W, Just S, Wessels G, Trano N, Most P, Katus HA et al. VEGF-PLCgamma1 pathway controls cardiac contractility in the embryonic heart. Genes Dev 2005; 19: 1624–1634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Chintalgattu V, Nair DM, Katwa LC . Cardiac myofibroblasts: a novel source of vascular endothelial growth factor (VEGF) and its receptors Flt-1 and KDR. J Mol Cell Cardiol 2003; 35: 277–286.

    Article  CAS  PubMed  Google Scholar 

  93. Tang JM, Wang JN, Zhang L, Zheng F, Yang JY, Kong X et al. VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. Cardiovasc Res 2011; 91: 402–411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chen HX, Cleck JN . Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol 2009; 6: 465–477.

    Article  CAS  PubMed  Google Scholar 

  95. Stewart DJ, Kutryk MJ, Fitchett D, Freeman M, Camack N, Su Y et al. VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: results of the NORTHERN trial. Mol Ther 2009; 17: 1109–1115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The financial support from Advanced Grant 20090506 from the European Research Council (ERC) is acknowledged. We thank Suzanne Kerbavcic for excellent editorial assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M Giacca.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Giacca, M., Zacchigna, S. VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond. Gene Ther 19, 622–629 (2012). https://doi.org/10.1038/gt.2012.17

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2012.17

Keywords

This article is cited by

Search

Quick links