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.

  • Review
  • Published:

Gene therapy progress and prospects: therapeutic angiogenesis for ischemic cardiovascular disease

Abstract

During the past decade, both in vitro and in vivo studies have provided new insights into the cellular and molecular mechanisms that govern angiogenesis and arteriogenesis. However, therapeutic angiogenesis clinical trials using recombinant protein or gene therapy formulations of single angiogenic growth factors have yielded at best only modest success to date. Among the second generation of angiogenic agents are therapeutic transgenes that enhance expression of two or more proangiogenic cytokines. These include synthetic constructs that mimic that activity of endogenous transcriptional regulators and other upstream, regulatory factors that have the potential to induce formation of morphologically and physiologically functional vessels. These agents are now beginning to be evaluated in clinical trials for patients with advanced ischemic cardiac and peripheral vascular disease.

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

Access options

Buy this article

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

Figure 1

Similar content being viewed by others

References

  1. Kipshidze NN, Tsapenko MV, Leon MB, Stone GW, Moses JW . Update on drug-eluting coronary stents. Expert Rev Cardiovasc Ther 2005; 3: 953–968.

    CAS  PubMed  Google Scholar 

  2. Stettler C, Allemann S, Egger M, Windecker S, Meier B, Diem P . Efficacy of drug eluting stents in patients with and without diabetes mellitus: indirect comparison of controlled trials. Heart 2006; 92: 650–657.

    CAS  PubMed  Google Scholar 

  3. Salam AM, Al Suwaidi J, Holmes Jr DR . Drug-eluting coronary stents. Curr Probl Cardiol 2006; 31: 8–119.

    PubMed  Google Scholar 

  4. Arora R, Sowers JR, Saunders E, Probstfield J, Lazar HL . Cardioprotective strategies to improve long-term outcomes following coronary artery bypass surgery. J Card Surg 2006; 21: 198–204.

    PubMed  Google Scholar 

  5. Likosky DS, Nugent WC, Ross CS . Improving outcomes of cardiac surgery through cooperative efforts: the northern New England experience. Semin Cardiothorac Vasc Anesth 2005; 9: 119–121.

    PubMed  Google Scholar 

  6. Serruys PW, Sianos G, Abizaid A, Aoki J, den Heijer P, Bonnier H et al. The effect of variable dose and release kinetics on neointimal hyperplasia using a novel paclitaxel-eluting stent platform: the Paclitaxel In-Stent Controlled Elution Study (PISCES). J Am Coll Cardiol 2005; 46: 253–260.

    CAS  PubMed  Google Scholar 

  7. Colombo A, Cosgrave J . Paclitaxel-eluting stents in complex lesions. JAMA 2005; 294: 1268–1270.

    CAS  PubMed  Google Scholar 

  8. Klein LW . Are drug-eluting stents the preferred treatment for multivessel coronary artery disease? J Am Coll Cardiol 2006; 47: 22–26.

    CAS  PubMed  Google Scholar 

  9. Aronow WS . Management of peripheral arterial disease. Cardiol Rev 2005; 13: 61–68.

    PubMed  Google Scholar 

  10. Wann-Hansson C, Hallberg IR, Risberg B, Lundell A, Klevsgard R . Health-related quality of life after revascularization for peripheral arterial occlusive disease: long-term follow-up. J Adv Nurs 2005; 51: 227–235.

    PubMed  Google Scholar 

  11. Simons M . Angiogenesis: where do we stand now? Circulation 2005; 111: 1556–1566.

    PubMed  Google Scholar 

  12. Carmeliet P . Angiogenesis in life, disease and medicine. Nature 2005; 438: 932–936.

    CAS  PubMed  Google Scholar 

  13. Papayannopoulou T . Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization. Blood 2004; 103: 1580–1585.

    CAS  PubMed  Google Scholar 

  14. Asahara T, Kawamoto A . Endothelial progenitor cells for postnatal vasculogenesis. Am J Physiol Cell Physiol 2004; 287: C572–C579.

    CAS  PubMed  Google Scholar 

  15. Armulik A, Abramsson A, Betsholtz C . Endothelial/pericyte interactions. Circ Res 2005; 97: 512–523.

    CAS  PubMed  Google Scholar 

  16. Rundhaug JE . Matrix metalloproteinases and angiogenesis. J Cell Mol Med 2005; 9: 267–285.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Yu J, deMuinck ED, Zhuang Z, Drinane M, Kauser K, Rubanyi GM et al. Endothelial nitric oxide synthase is critical for ischemic remodeling, mural cell recruitment, and blood flow reserve. Proc Natl Acad Sci USA 2005; 102: 10999–11004.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Hagedorn M, Balke M, Schmidt A, Bloch W, Kurz H, Javerzat S et al. VEGF coordinates interaction of pericytes and endothelial cells during vasculogenesis and experimental angiogenesis. Dev Dyn 2004; 230: 23–33.

    CAS  PubMed  Google Scholar 

  19. Lehti K, Allen E, Birkedal-Hansen H, Holmbeck K, Miyake Y, Chun TH et al. An MT1-MMP-PDGF receptor-beta axis regulates mural cell investment of the microvasculature. Genes Dev 2005; 19: 979–991.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Heil M, Schaper W . Influence of mechanical, cellular, and molecular factors on collateral artery growth (arteriogenesis). Circ Res 2004; 95: 449–458.

    CAS  PubMed  Google Scholar 

  21. Ho TK, Rajkumar V, Ponticos M, Leoni P, Black DC, Abraham DJ et al. Increased endogenous angiogenic response and hypoxia-inducible factor-1alpha in human critical limb ischemia. J Vasc Surg 2006; 43: 125–133.

    PubMed  Google Scholar 

  22. Shirakawa Y, Sawa Y, Takewa Y, Tatsumi E, Kaneda Y, Taenaka Y et al. Gene transfection with human hepatocyte growth factor complementary DNA plasmids attenuates cardiac remodeling after acute myocardial infarction in goat hearts implanted with ventricular assist devices. J Thorac Cardiovasc Surg 2005; 130: 624–632.

    CAS  PubMed  Google Scholar 

  23. Cao R, Eriksson A, Kubo H, Alitalo K, Cao Y, Thyberg J . Comparative evaluation of FGF-2-, VEGF-A-, and VEGF-C-induced angiogenesis, lymphangiogenesis, vascular fenestrations, and permeability. Circ Res 2004; 94: 664–670.

    CAS  PubMed  Google Scholar 

  24. Ferrara N, Kerbel RS . Angiogenesis as a therapeutic target. Nature 2005; 438: 967–974.

    CAS  PubMed  Google Scholar 

  25. Vincent KA, Kelly RA . Integrative Pro-Angiogenic Activation Therapeutic Neovascularization. Springer Life Sciences: New York, NY, USA, 2006.

    Google Scholar 

  26. Annex BH, Simons M . Growth factor-induced therapeutic angiogenesis in the heart: protein therapy. Cardiovasc Res 2005; 65: 649–655.

    CAS  PubMed  Google Scholar 

  27. Frantz S, Vincent KA, Feron O, Kelly RA . Innate immunity and angiogenesis. Circ Res 2005; 96: 15–26.

    CAS  PubMed  Google Scholar 

  28. 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.

    CAS  PubMed  Google Scholar 

  29. Lekas M, Lekas P, Latter DA, Kutryk MB, Stewart DJ . Growth factor-induced therapeutic neovascularization for ischaemic vascular disease: time for a re-evaluation? Curr Opin Cardiol 2006; 21: 376–384.

    PubMed  Google Scholar 

  30. Tirziu D, Simons M . Angiogenesis in the human heart: gene and cell therapy. Angiogenesis 2005; 8: 241–251.

    PubMed  Google Scholar 

  31. Gounis MJ, Spiga MG, Graham RM, Wilson A, Haliko S, Lieber BB et al. Angiogenesis is confined to the transient period of VEGF expression that follows adenoviral gene delivery to ischemic muscle. Gene Therapy 2005; 12: 762–771.

    CAS  PubMed  Google Scholar 

  32. Zheng Y, Murakami M, Takahashi H, Yamauchi M, Kiba A, Yamaguchi S et al. Chimeric VEGF-E(NZ7)/PlGF promotes angiogenesis via VEGFR-2 without significant enhancement of vascular permeability and inflammation. Arterioscler Thromb Vasc Biol 2006; 26: 2019–2026.

    CAS  PubMed  Google Scholar 

  33. Morishita R, Aoki M, Hashiya N, Makino H, Yamasaki K, Azuma J et al. Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease. Hypertension 2004; 44: 203–209.

    CAS  PubMed  Google Scholar 

  34. Nikol S, Murphy SA, Gibson CM . Therapeutic angiogenesis with intramuscular NV1FGF in patients with critical limb ischemia. Am Coll Cardiol 2006, Abstract.

  35. Semenza GL . Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology (Bethesda) 2004; 19: 176–182.

    CAS  Google Scholar 

  36. Lahiri S, Roy A, Baby SM, Hoshi T, Semenza GL, Prabhakar NR . Oxygen sensing in the body. Prog Biophys Mol Biol 2006; 91: 249–286.

    CAS  PubMed  Google Scholar 

  37. Schofield CJ, Ratcliffe PJ . Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 2004; 5: 343–354.

    CAS  PubMed  Google Scholar 

  38. Trentin D, Hall H, Wechsler S, Hubbell JA . Peptide-matrix-mediated gene transfer of an oxygen-insensitive hypoxia-inducible factor-1alpha variant for local induction of angiogenesis. Proc Natl Acad Sci USA 2006; 103: 2506–2511.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Patel TH, Kimura H, Weiss CR, Semenza GL, Hofmann LV . Constitutively active HIF-1alpha improves perfusion and arterial remodeling in an endovascular model of limb ischemia. Cardiovasc Res 2005; 68: 144–154.

    CAS  PubMed  Google Scholar 

  40. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004; 10: 858–864.

    CAS  PubMed  Google Scholar 

  41. Ceradini DJ, Gurtner GC . Homing to hypoxia: HIF-1 as a mediator of progenitor cell recruitment to injured tissue. Trends Cardiovasc Med 2005; 15: 57–63.

    CAS  PubMed  Google Scholar 

  42. Phillips RJ, Mestas J, Gharaee-Kermani M, Burdick MD, Sica A, Belperio JA et al. Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1alpha. J Biol Chem 2005; 280: 22473–22481.

    CAS  PubMed  Google Scholar 

  43. Hirota K, Semenza GL . Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol Hematol 2006; 59: 15–26.

    PubMed  Google Scholar 

  44. Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 2006; 124: 175–189.

    CAS  PubMed  Google Scholar 

  45. Pajusola K, Kunnapuu J, Vuorikoski S, Soronen J, Andre H, Pereira T et al. Stabilized HIF-1alpha is superior to VEGF for angiogenesis in skeletal muscle via adeno-associated virus gene transfer. FASEB J 2005; 19: 1365–1367.

    CAS  PubMed  Google Scholar 

  46. Heinl-Green A, Radke PW, Munkonge FM, Frass O, Zhu J, Vincent K et al. The efficacy of a ‘master switch gene’ HIF-1alpha in a porcine model of chronic myocardial ischaemia. Eur Heart J 2005; 26: 1327–1332.

    CAS  PubMed  Google Scholar 

  47. Luo Y, Jiang C, Belanger AJ, Akita GY, Wadsworth SC, Gregory RJ et al. Constitutively active hypoxia-inducible factor-1alpha/VP16 hybrid factor activates expression of the human B-type natriuretic peptide gene. Mol Pharmacol 2006; 69: 1953–1962.

    CAS  PubMed  Google Scholar 

  48. Wilhide ME, Jones WK . Potential therapeutic gene for the treatment of ischemic disease: Ad2/hypoxia-inducible factor-1alpha (HIF-1)/VP16 enhances B-type natriuretic peptide gene expression via a HIF-1-responsive element. Mol Pharmacol 2006; 69: 1773–1778.

    CAS  PubMed  Google Scholar 

  49. Kido M, Du L, Sullivan CC, Li X, Deutsch R, Jamieson SW et al. Hypoxia-inducible factor 1-alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse. J Am Coll Cardiol 2005; 46: 2116–2124.

    CAS  PubMed  Google Scholar 

  50. Date T, Mochizuki S, Belanger AJ, Yamakawa M, Luo Z, Vincent KA et al. Expression of constitutively stable hybrid hypoxia-inducible factor-1alpha protects cultured rat cardiomyocytes against simulated ischemia–reperfusion injury. Am J Physiol Cell Physiol 2005; 288: C314–C320.

    CAS  PubMed  Google Scholar 

  51. Natarajan R, Salloum FN, Fisher BJ, Kukreja RC, Fowler III AA . Hypoxia inducible factor-1 activation by prolyl 4-hydroxylase-2 gene silencing attenuates myocardial ischemia reperfusion injury. Circ Res 2006; 98: 133–140.

    CAS  PubMed  Google Scholar 

  52. Siddiq A, Ayoub IA, Chavez JC, Aminova L, Shah S, LaManna JC et al. Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system. J Biol Chem 2005; 280: 41732–41743.

    CAS  PubMed  Google Scholar 

  53. Baek JH, Mahon PC, Oh J, Kelly B, Krishnamachary B, Pearson M et al. OS-9 interacts with hypoxia-inducible factor 1alpha and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1alpha. Mol Cell 2005; 17: 503–512.

    CAS  PubMed  Google Scholar 

  54. Flashman E, McDonough MA, Schofield CJ . OS-9: another piece in the HIF complex story. Mol Cell 2005; 17: 472–473.

    CAS  PubMed  Google Scholar 

  55. Elvidge GP, Glenny L, Appelhoff RJ, Ratcliffe PJ, Ragoussis J, Gleadle JM . Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1alpha, HIF-2alpha, and other pathways. J Biol Chem 2006; 281: 15215–15226.

    CAS  PubMed  Google Scholar 

  56. Diaz-Gonzalez JA, Russell J, Rouzaut A, Gil-Bazo I, Montuenga L . Targeting hypoxia and angiogenesis through HIF-1alpha inhibition. Cancer Biol Ther 2005; 4: 1055–1062.

    CAS  PubMed  Google Scholar 

  57. Safran M, Kim WY, O'Connell F, Flippin L, Gunzler V, Horner JW et al. Mouse model for noninvasive imaging of HIF prolyl hydroxylase activity: assessment of an oral agent that stimulates erythropoietin production. Proc Natl Acad Sci USA 2006; 103: 105–110.

    CAS  PubMed  Google Scholar 

  58. Huang Y, Hickey RP, Yeh JL, Liu D, Dadak A, Young LH et al. Cardiac myocyte-specific HIF-1alpha deletion alters vascularization, energy availability, calcium flux, and contractility in the normoxic heart. FASEB J 2004; 18: 1138–1140.

    CAS  PubMed  Google Scholar 

  59. Kim JW, Tchernyshyov I, Semenza GL, Dang CV . HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006; 3: 177–185.

    PubMed  Google Scholar 

  60. Takeda N, Maemura K, Imai Y, Harada T, Kawanami D, Nojiri T et al. Endothelial PAS domain protein 1 gene promotes angiogenesis through the transactivation of both vascular endothelial growth factor and its receptor, Flt-1. Circ Res 2004; 95: 146–153.

    CAS  PubMed  Google Scholar 

  61. Walmsley SR, Cadwallader KA, Chilvers ER . The role of HIF-1alpha in myeloid cell inflammation. Trends Immunol 2005; 26: 434–439.

    CAS  PubMed  Google Scholar 

  62. Zarember KA, Malech HL . HIF-1alpha: a master regulator of innate host defenses? J Clin Invest 2005; 115: 1702–1704.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Hellwig-Burgel T, Stiehl DP, Wagner AE, Metzen E, Jelkmann W . Review: hypoxia-inducible factor-1 (HIF-1): a novel transcription factor in immune reactions. J Interferon Cytokine Res 2005; 25: 297–310.

    PubMed  Google Scholar 

  64. Peyssonnaux C, Datta V, Cramer T, Doedens A, Theodorakis EA, Gallo RL et al. HIF-1alpha expression regulates the bactericidal capacity of phagocytes. J Clin Invest 2005; 115: 1806–1815.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Heil M, Eitenmuller I, Schmitz-Rixen T, Schaper W . Arteriogenesis versus angiogenesis: similarities and differences. J Cell Mol Med 2006; 10: 45–55.

    CAS  PubMed  Google Scholar 

  66. Eitenmuller I, Volger O, Kluge A, Troidl K, Barancik M, Cai WJ et al. The range of adaptation by collateral vessels after femoral artery occlusion. Circ Res 2006; 99: 656–662.

    PubMed  Google Scholar 

  67. Oda T, Hirota K, Nishi K, Takabuchi S, Oda S, Yamada H et al. Activation of hypoxia-inducible factor 1 during macrophage differentiation. Am J Physiol Cell Physiol 2006; 291: C104–C113.

    CAS  PubMed  Google Scholar 

  68. Kempf VA, Lebiedziejewski M, Alitalo K, Walzlein JH, Ehehalt U, Fiebig J et al. Activation of hypoxia-inducible factor-1 in bacillary angiomatosis: evidence for a role of hypoxia-inducible factor-1 in bacterial infections. Circulation 2005; 111: 1054–1062.

    CAS  PubMed  Google Scholar 

  69. Zhang W, Petrovic JM, Callaghan D, Jones A, Cui H, Howlett C et al. Evidence that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of interleukin-1beta (IL-1beta) in astrocyte cultures. J Neuroimmunol 2006; 174: 63–73.

    CAS  PubMed  Google Scholar 

  70. Louis NA, Hamilton KE, Kong T, Colgan SP . HIF-dependent induction of apical CD55 coordinates epithelial clearance of neutrophils. FASEB J 2005; 19: 950–959.

    CAS  PubMed  Google Scholar 

  71. Neumann AK, Yang J, Biju MP, Joseph SK, Johnson RS, Haase VH et al. Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction. Proc Natl Acad Sci USA 2005; 102: 17071–17076.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Althaus J, Bernaudin M, Petit E, Toutain J, Touzani O, Rami A . Expression of the gene encoding the pro-apoptotic BNIP3 protein and stimulation of hypoxia-inducible factor-1alpha (HIF-1alpha) protein following focal cerebral ischemia in rats. Neurochem Int 2006; 48: 687–695.

    CAS  PubMed  Google Scholar 

  73. van Royen N, Schirmer SH, Atasever B, Behrens CY, Ubbink D, Buschmann EE et al. START Trial: a pilot study on STimulation of ARTeriogenesis using subcutaneous application of granulocyte–macrophage colony-stimulating factor as a new treatment for peripheral vascular disease. Circulation 2005; 112: 1040–1046.

    CAS  PubMed  Google Scholar 

  74. Post MJ, Sato K, Murakami M, Bao J, Tirziu D, Pearlman JD et al. Adenoviral PR39 improves blood flow and myocardial function in a pig model of chronic myocardial ischemia by enhancing collateral formation. Am J Physiol Regul Integr Comp Physiol 2006; 290: R494–R500.

    CAS  PubMed  Google Scholar 

  75. Muinck ED, Nagy N, Tirziu D, Murakami M, Gurusamy N, Boswami SK et al. Protection against myocardial ischemia–reperfusion injury by the angiogenic masterswitch protein PR39 gene therapy: the roles of HIF-1alpha stabilization and FGFR1 signaling. Antioxid Redox Signal 2007; 9: 437–445.

    PubMed  Google Scholar 

  76. Wu J, Parungo C, Wu G, Kang PM, Laham RJ, Sellke FW et al. PR39 inhibits apoptosis in hypoxic endothelial cells: role of inhibitor apoptosis protein-2. Circulation 2004; 109: 1660–1667.

    CAS  PubMed  Google Scholar 

  77. Shie JL, Wu G, Wu J, Liu FF, Laham RJ, Oettgen P et al. RTEF-1, a novel transcriptional stimulator of vascular endothelial growth factor in hypoxic endothelial cells. J Biol Chem 2004; 279: 25010–25016.

    CAS  PubMed  Google Scholar 

  78. Mizukami Y, Fujiki K, Duerr EM, Gala M, Jo WS, Zhang X et al. Hypoxic regulation of vascular endothelial growth factor through the induction of phosphatidylinositol 3-kinase/Rho/ROCK and c-Myc. J Biol Chem 2006; 281: 13957–13963.

    CAS  PubMed  Google Scholar 

  79. Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 2005; 9: 617–628.

    CAS  PubMed  Google Scholar 

  80. Sainson RC, Harris AL . Hypoxia-regulated differentiation: let's step it up a Notch. Trends Mol Med 2006; 12: 141–143.

    CAS  PubMed  Google Scholar 

  81. Hilfiker-Kleiner D, Hilfiker A, Fuchs M, Kaminski K, Schaefer A, Schieffer G et al. Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ Res 2004; 95: 187–195.

    CAS  PubMed  Google Scholar 

  82. Ingley E, Klinken SP . Cross-regulation of JAK and Src kinases. Growth Factors 2006; 24: 89–95.

    CAS  PubMed  Google Scholar 

  83. Hilfiker-Kleiner D, Limbourg A, Drexler H . STAT3-mediated activation of myocardial capillary growth. Trends Cardiovasc Med 2005; 15: 152–157.

    CAS  PubMed  Google Scholar 

  84. Hilfiker-Kleiner D, Hilfiker A, Kaminski K, Schaefer A, Park JK, Michel K et al. Lack of JunD promotes pressure overload-induced apoptosis, hypertrophic growth, and angiogenesis in the heart. Circulation 2005; 112: 1470–1477.

    PubMed  Google Scholar 

  85. Bhattacharya S, Macdonald ST, Farthing CR . Molecular mechanisms controlling the coupled development of myocardium and coronary vasculature. Clin Sci (Lond) 2006; 111: 35–46.

    CAS  Google Scholar 

  86. Gommans WM, Haisma HJ, Rots MG . Engineering zinc finger protein transcription factors: the therapeutic relevance of switching endogenous gene expression on or off at command. J Mol Biol 2005; 354: 507–519.

    CAS  PubMed  Google Scholar 

  87. Yu J, Lei L, Hinh L, Hickey RP, Huang Y, Liu D 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.

    CAS  PubMed  Google Scholar 

  88. 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.

    CAS  PubMed  Google Scholar 

  89. Xie D, Li Y, Reed EA, Odronic SI, Kontos CD, Annex BH . An engineered vascular endothelial growth factor-activating transcription factor induces therapeutic angiogenesis in ApoE knockout mice with hindlimb ischemia. J Vasc Surg 2006; 44: 166–175.

    PubMed  Google Scholar 

  90. Lucerna M, Pomyje J, Mechtcheriakova D, Kadl A, Gruber F, Bilban M et al. Sustained expression of early growth response protein-1 blocks angiogenesis and tumor growth. Cancer Res 2006; 66: 6708–6713.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Khachigian LM . Early growth response-1 in cardiovascular pathobiology. Circ Res 2006; 98: 186–191.

    CAS  PubMed  Google Scholar 

  92. Worden B, Yang XP, Lee TL, Bagain L, Yeh NT, Cohen JG et al. Hepatocyte growth factor/scatter factor differentially regulates expression of proangiogenic factors through Egr-1 in head and neck squamous cell carcinoma. Cancer Res 2005; 65: 7071–7080.

    CAS  PubMed  Google Scholar 

  93. Heil M, Schaper W . Arteriogenic growth factors, chemokines and proteases as a prerequisite for arteriogenesis. Drug News Perspect 2005; 18: 317–322.

    CAS  PubMed  Google Scholar 

  94. Schalch P, Patejunas G, Retuerto M, Sarateanu S, Milbrandt J, Thakker G et al. Homozygous deletion of early growth response 1 gene and critical limb ischemia after vascular ligation in mice: evidence for a central role in vascular homeostasis. J Thorac Cardiovasc Surg 2004; 128: 595–601.

    CAS  PubMed  Google Scholar 

  95. Stamatovic SM, Dimitrijevic OB, Keep RF, Andjelkovic AV . Inflammation and brain edema: new insights into the role of chemokines and their receptors. Acta Neurochir Suppl 2006; 96: 444–450.

    CAS  PubMed  Google Scholar 

  96. Hashiya N, Jo N, Aoki M, Matsumoto K, Nakamura T, Sato Y et al. In vivo evidence of angiogenesis induced by transcription factor Ets-1: Ets-1 is located upstream of angiogenesis cascade. Circulation 2004; 109: 3035–3041.

    CAS  PubMed  Google Scholar 

  97. Martin P, Parkhurst SM . Parallels between tissue repair and embryo morphogenesis. Development 2004; 131: 3021–3034.

    CAS  PubMed  Google Scholar 

  98. Mace KA, Hansen SL, Myers C, Young DM, Boudreau N . HOXA3 induces cell migration in endothelial and epithelial cells promoting angiogenesis and wound repair. J Cell Sci 2005; 118: 2567–2577.

    CAS  PubMed  Google Scholar 

  99. Matsuki A, Yamamoto S, Nakagami H, Aoki M, Tamai K, Matsumoto K et al. No influence of tumor growth by intramuscular injection of hepatocyte growth factor plasmid DNA: safety evaluation of therapeutic angiogenesis gene therapy in mice. Biochem Biophys Res Commun 2004; 315: 59–65.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R A Kelly.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vincent, K., Jiang, C., Boltje, I. et al. Gene therapy progress and prospects: therapeutic angiogenesis for ischemic cardiovascular disease. Gene Ther 14, 781–789 (2007). https://doi.org/10.1038/sj.gt.3302953

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302953

Keywords

This article is cited by

Search

Quick links