Molecular Biotechnology

, Volume 22, Issue 2, pp 153–164 | Cite as

Gene transfer to the vasculature

Historical perspective and implication for future research objectives
  • Sarah J. George
  • Andrew H. Baker


Cardiovascular diseases are a major cause of fatality, disability, and economic burden in Western civilization. Although the pharmaceutical industry has delivered a plethora of drugs for treatment of diverse cardiovascular complaints, there remain many conditions for which pharmacological regimens are either nonexistent or largely ineffective. In contrast, remarkable progress has been made in the field of vascular gene transfer in the last decade. The vast majority of studies are preclinical, although a number of high profile vascular gene therapy clinical trials are in progress. In principle, vascular gene therapy represents an unprecedented opportunity to treat a host of cardiovascular diseases in humans although many scientific, clinical, and ethical obstacles remain. Here we discuss the rapid progress in preclinical vascular gene therapy, highlight the most appropriate gene delivery vectors, and discuss the advances toward the ultimate goal of an efficient and safe gene therapy for diverse cardiovascular diseases.

Index Entries

Gene therapy cardiovascular disease viral-vectors atherosclerosis restenosis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Nabel, E. G., Plautz, G., Nabel, G. J. (1990) Site-specific gene expression in vivo by direct gene transfer into the arterial wall. Science 249, 1285–1288.PubMedCrossRefGoogle Scholar
  2. 2.
    Yla-Herttuala, S. and Martin, J. F. (2000) Cardiovascular gene therapy. Lancet 355, 213–222.PubMedCrossRefGoogle Scholar
  3. 3.
    Libby, P. (1998) Gene therapy of restenosis Promise and perils. Circ. Res. 82(3), 404–406.PubMedGoogle Scholar
  4. 4.
    Baker, A. H., Mehta, D., George, S. J., and Angelini, G. D. (1997) Prevention of vein graft failure: potential applications for gene therapy. Cardiovasc. Res. 35, 442–450.PubMedCrossRefGoogle Scholar
  5. 5.
    Stephan, D. J., Yang, Z.-Y., San, H., R.D. S., Wheeler, C. J., Felgner, P. L., Gordon, D., Nabel, G. J., and Nabel, E. G. (1996) A new cationic liposome DNA complex enhances the efficiency of arterial gene transfer in vivo. Hum. Gene Ther. 7(15), 1803–1812.PubMedGoogle Scholar
  6. 6.
    Turunen, M. P., Hiltunen, M. O., Ruponen, M., Virkamaki, L., Szoka, F. C. J., Urtti, A., and Yla-Herttuala, S. (1999) Efficient adventitial gene delivery to rabbit carotid artery with cationic polymer-plasmid complexes. Gene Therapy 6(1), 6–11.PubMedCrossRefGoogle Scholar
  7. 7.
    Hart, S. L., Harbottle, R. P., Cooper, R., Miller, A., Williamson, R., and Coutelle, C. (1995) Gene delivery and expression mediated by an integrin-binding peptide. Gene Therapy 2(8), 552–554.PubMedGoogle Scholar
  8. 8.
    Harbottle, R. P., Cooper, R. G., Hart, S. L., Ladhoff, A., McKay, T., Knight, A. M., Wagner, E., Miller, A. D., and Coutelle, C. (1998) An RGD-oligolysine peptide: A prototype construct for integrin-mediated gene delivery. Hum. Gene Ther. 9(7), 1037–1047.PubMedGoogle Scholar
  9. 9.
    Sabaawy, H. E., Zhang, F., Nguyen, X. D., ElHosseiny, A., Nasjletti, A., Schwartzman, M., Dennery, P., Kappas, A., and Abraham, N. G. (2001) Human heme oxygenase-1 gene transfer lowers blood pressure and promotes growth in spontaneously hypertensive rats. Hypertension 38(2), 210–215.PubMedGoogle Scholar
  10. 10.
    Bennett, M. R., Littlewood, T. D., Schwartz, S. M., Weissberg, P. L. (1997) Increased sensitivity of human vascular smooth muscle cells from atherosclerotic plaques to p53-mediated apoptosis. Circ. Res. 81(4), 591–599.PubMedGoogle Scholar
  11. 11.
    Naldini, L., Blomer, U., Gage, F. H., Trono, D., Verma, I. M. (1996) Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc. Natl. Acad. Sci. USA 93(21), 11,382–11,388.CrossRefGoogle Scholar
  12. 12.
    Lee, R. J., Springer, M. L., Blanco-Bose, W. E., Shaw, R., Ursell, P. C., and Blau, H. M. (2000) VEGF gene delivery to myocardium. Deleterious effects of unregulated expression. Circulation 102, 898–901.PubMedGoogle Scholar
  13. 13.
    Graham, F. L. and Prevec, L. (1992) Adenovirus-based expression vectors and recombinant vaccine, in Vaccines: New approaches to immunological problems. Ellis, R. W. (ed.) Butterworth-Heinemann: Boston. 363–390.Google Scholar
  14. 14.
    Bett, A. J., Haddara, W., Prevec, L., and Graham, F. L. (1994) An efficient and flexible system for construction of adenovirus vectors with insertions or deletions in early regions 1 and 3. Proc. Natl. Acad. Sci. USA 91, 8802–8806.PubMedCrossRefGoogle Scholar
  15. 15.
    Hedman, M. and Yla-Herttuala, S. (2000) Gene therapy for treatment of peripheral vascular disease and coronary artery disease. Drugs of Today 36(9), 609–617.PubMedGoogle Scholar
  16. 16.
    Newman, K. D., Dunn, P. F., Owens, J. W., et al. (1995) Adenovirus-mediated gene transfer into normal rabbit arteries results in prolonged vascular cell activation, inflammation, and neointimal hyperplasia. J. Clin. Invest. 96(6), 2955–2965.PubMedGoogle Scholar
  17. 17.
    Wen, S., Schneider, D. B., Driscoll, R. M., Vassalli, G., Sassani, A. B., and Dichek, D.A. (2000) Second-generation adenoviral vectors do not prevent rapid loss of transgene expression and vector DNA from the arterial wall. Arterioscler Thromb. Vasc. Biol. 20, 1452–1458.PubMedGoogle Scholar
  18. 18.
    Havenga, M. J. E., Lemckert, A. A. C., Grimbergen, J. M., et al. (2001) Improved adenovirus vectors for infection of cardiovascular tissues. J. Virol. 75(7), 3335–3342.PubMedCrossRefGoogle Scholar
  19. 19.
    Qian, H. S., Channon, K., Neplioueva, V., et al. (2001) Improved adenoviral vector for vascular gene therapy — Beneficial effects on vascular function and inflammation. Circ. Res. 88(9), 911–917.PubMedCrossRefGoogle Scholar
  20. 20.
    Surosky, R. T., Urabe, M., Godwin, S. G., et al. (1997) Adeno-associated virus Rep proteins target DNA sequences to a unique locus in the human genome. J. Virol. 71(10), 7951–7959.PubMedGoogle Scholar
  21. 21.
    Wagner, J. A., Messner, A. H., Moran, M. L., et al. (1999) Safety and biological efficacy of an adeno-associated virus vector-cystic fibrosis transmembrane regulator (AAV-CFTR) in the cystic fibrosis maxillary sinus. Laryngoscope 109(2 I), 266–274.PubMedCrossRefGoogle Scholar
  22. 22.
    Stedman, H., Wilson, J. M., Finke, R., Kleckner, A. L., and Mendell, J., Phase I clinical trial utilizing gene therapy for limb girdle muscular dystrophy: a-, b-, g, or f-sarcoglycan gene delivered with tramuscular instillations of adeno-associated vectors. Hum. Gene Ther. 11, 777–790.Google Scholar
  23. 23.
    Ponnazhagan, S., Erikson, D., Kearns, W. G., et al. (1997) Lack of site-specific integration of the recombinant adeno-associated virus 2 genomes in human cells. Hum. Gene Ther. 8(3), 275–284.PubMedGoogle Scholar
  24. 24.
    Nakai, H., Yant, S. R., Storm, T. A., Fuess, S., Meuse, L, and Kay, M. A. (2001) Extrachromosomal recombinant adeno-associated virus vector genomes are primarily responsible for stable liver transduction in vivo. J. Virol. 75(15), 6969–6976.PubMedCrossRefGoogle Scholar
  25. 25.
    Donsante, A., Vogler, C., Muzyczka, N., et al. (2001) Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors. Gene Ther. 8(17), 1343–1346.PubMedCrossRefGoogle Scholar
  26. 26.
    Phillips, M. I. (1999) Gene therapy for hypertension. Drug News & Perspectives 12(1), 21–26.CrossRefGoogle Scholar
  27. 27.
    Wilson, J. M., Birinyi, L. K., Salomom, R. N., Libby, P., Callow, A. D., and Mulligan, R. C. (1989) Implantation of vascular grafts lined with genetically modified endothelial cells. Science 244, 1344–1346.PubMedCrossRefGoogle Scholar
  28. 28.
    Nabel, E. G., Plautz, G., Boyce, F. M., Stanley, J. C., and Nabel, G. J. (1989) Recombinant gene expression in vivo within endothelial cells of the arterial wall. Science 244, 1342–1344.PubMedCrossRefGoogle Scholar
  29. 29.
    Lynch, C. M., Clowes, M. M., Osborne, W. R. A., Clowes, A. W., A.D., M. (1992) Long-term expression of human adenosine deaminase in vascular smooth muscle cells of rats: A model for gene therapy. Proc Natl Acad Sci USA 89, 1138–1142.PubMedCrossRefGoogle Scholar
  30. 30.
    Plautz, G., Nabel, E., and Nabel, G. J. (1991) Introduction of vascular smooth muscle cells expressing recombinant genes in vivo. Circulation 83, 578–583.PubMedGoogle Scholar
  31. 31.
    Dichek, D. A., Neville, R. F., Zwiebel, J. A., Freeman, S. M., Leon, M. B., and Anderson, W.F. (1989) Seeding of intravascular stents with genetically engineered endothelial cells. Circulation 80, 1347–1353.PubMedGoogle Scholar
  32. 32.
    Messina, L. M., Podrazik, R. M., Whitehill, T. A., et al. (1992) Adhesion and incorporation of lacZ-transduced endothelial cells into the intact capillary wall in the rat. Proc. Natl. Acad. Sci. USA 89, 12,018–12,022.CrossRefGoogle Scholar
  33. 33.
    Kullo, I. J., Simari, R. D., and Schwartz, R. S. (1999) Vascular gene transfer. From bench to bedside. Arterioscler. Thromb. Vasc. Biol. 19, 196–207.PubMedGoogle Scholar
  34. 34.
    Chen, S. J., Wilson, J. M., and Muller, D. W. M. (1994) Adenovirus-mediated gene transfer of soluble vascular cell adhesion molecule to porcine interposition vein grafts. Circulation 89, 1922–1928.PubMedGoogle Scholar
  35. 35.
    Takeshita, S., Losordo, D. W., Kearney, M., Rossow, S. T., and Isner, J. M. (1994) Time course of recombinant protein secretion after liposome-mediated gene transfer in a rabbit arterial organ culture model. Lab. Invest. 71(3), 387–391.PubMedGoogle Scholar
  36. 36.
    Kupfer, J. M., Ruan, X. M., Liu, G., Matloff, J., Forrester, J., and Chaux, A. (1994) High-efficiency gene transfer to autologous rabbit jugular vein grafts using adenovirus-transferrin/polylysine-DNA complexes. Hum. Gene Ther. 5, 1437–1443.PubMedGoogle Scholar
  37. 37.
    George, S. J., Baker, A. H., Angelini, G. D., and Newby, A. C. (1998) Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins. Gene Therapy 5, 1552–1560.PubMedCrossRefGoogle Scholar
  38. 38.
    George, S. J., Johnson, J. L., Angelini, G. D., Newby, A. C., and Baker, A.H. (1998) Adenovirus-mediated gene transfer of the human TIMP-1 gene inhibits SMC migration and neointima formation in human saphenous vein. Hum. Gene Ther. 9, 867–877.PubMedGoogle Scholar
  39. 39.
    George, S. J., Lloyd, C. T., Angelini, G. D., Newby, A. C., and Baker, A. H. (2000) Inhibition of late vein graft neointima formation in human and porcine models by adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-3. Circulation 101, 296–304.PubMedGoogle Scholar
  40. 40.
    Shi, Y., Pieniek, M., Fard, A., O’Brien, J., Mannion, J. D., and Zalewski, A. (1996) Adventitial remodeling after coronary arterial injury. Circulation 93, 340–348.PubMedGoogle Scholar
  41. 41.
    Scott, N. A., Cipolla, G. D., Ross, C. E., Dunn, B., Martin, F. H., Simonet, L., and Wilcox, J. N. (1996) Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries. Circulation 93 2178–2187.PubMedGoogle Scholar
  42. 42.
    Barker, S. G. E., Tilling, L. C., Miller, G. C., Beesley, J. E., Fleetwood, G., Stavri, G. T., Baskerville, P. A., and Martin, J. F. (1994) The adventitia and atherogenesis — Removal initiates intimal proliferation in the rabbit which regresses on generation of a neo-adventitia. Atherosclerosis 105(2), 131–144.PubMedCrossRefGoogle Scholar
  43. 43.
    Chatelain, R. E. and Dardik, B. N. (1988) Increased DNA replication in the arterial adventitia after aortic ligation. Hypertension 11(suppl I), I130-I134.PubMedGoogle Scholar
  44. 44.
    Schneider, D. B., Sassani, A. B., Vassalli, G., Driscoll, R. M., Dichek, D. A. (1999) Adventitial delivery minimizes the proinflammatory effects of adenoviral vectors. J. Vasc. Surg. 29(3), 543–550.PubMedCrossRefGoogle Scholar
  45. 45.
    Kullo, I. J., Mozes, G., Schwartz, R.S., et al. (1997) Adventitial gene transfer of recombinant endothelial nitric oxide synthase to rabbit carotid arteries alters vascular reactivity. Circulation 96, 2254–2261.PubMedGoogle Scholar
  46. 46.
    Laitinen, M., Pakkanen, T., Donetti, E., et al. (1997) Gene transfer into carotid artery using an adventitial collar: comparison of the effectiveness of the plasmid liposome complexes, retroviruses, pseudotyped retroviruses, and adenoviruses. Human Gene Therapy 8, 1645–1650.PubMedGoogle Scholar
  47. 47.
    Rios, C. D., Ooboshi, H., Piegors, D., Davidson, B. L., Heistad, D. D. (1995) Adenovirus-mediated gene transfer to normal and atherosclerotic arteries. A novel approach. Arterioscler. Thromb. Vasc. Biol. 15, 2241–2245.PubMedGoogle Scholar
  48. 48.
    Pakkanen, T. M., Laitnen, M., Hippelainen, M., Hiltunen, M. O., Alhava, E., and Yla-Herttuala, S. (2000) Periadventitial lacZ gene transfer to pig carotid arteries using a biodegradable collagen collar or a wrap of collagen sheet with adenoviruses and plasmid-liposome complexes. J. Gene Med. 2, 52–60.PubMedCrossRefGoogle Scholar
  49. 49.
    Ooboshi, H., Welsh, M. J., Rios, C. D., Davidson, B. L., and Heistad, D. D. (1995) Adenovirus-mediated gene transfer in vivo to cerebral blood vessels and perivascular tissues. Circ. Res. 77, 7–13.PubMedGoogle Scholar
  50. 50.
    March, K. L., Woody, M., Mehdi, K., Zipes, D. P., Brantly, M., and Trapnell, L. (1999) Efficient in vivo catheter-based pericardial gene transfer mediated by adenoviral vectors. Clin. Cardiol. 22(Suppl 1), 123–129.Google Scholar
  51. 51.
    Mehdi, K., Wilensky, R. L., Baek, S. H., Trapnell, B. C., and March, K. L. (1996) Efficient adenovirus-mediated perivascular gene transfer and protein delivery by a transvascular injection catheter. J. Am. Coll. Cardiol. 27(Suppl A), 164A.Google Scholar
  52. 52.
    Reynolds, P. N., Nicklin, S. A., Kaliberova, L., et al. Combined transductional and transcriptional targeting improves the specificity of transgene expression in vivo. Nat. Biotechnol. 19(9), 838–842.Google Scholar
  53. 53.
    Wickham, T. J. (2000) Targeting adenovirus. Gene Therapy 7(2), 110–114.PubMedCrossRefGoogle Scholar
  54. 54.
    Nicklin, S. A., White, S. J., Watkins, S. J., Hawkins, R. E., and Baker, A. H. (2000) Selective targeting of gene transfer to vascular endothelial cells by use of peptides isolated by phage display. Circulation 102(2), 231–237.PubMedGoogle Scholar
  55. 55.
    White, S. J., Nicklin, S. A., Sawamura, T., Baker, A. H. (2001) Identification of peptides that target the endothelial cell-specific LOX-1 receptor. Hypertension 37(2), 449–455.PubMedGoogle Scholar
  56. 56.
    Rekhter, M. D., Simari, R. D., Work, C. W., Nabel, G. J., Nabel, E. G., and Gordon, D. (1998) Gene transfer into normal and atherosclerotic human blood vessels. Circ. Res. 82(12), 1243–1252.PubMedGoogle Scholar
  57. 57.
    Ross, R. (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362, 801–809.PubMedCrossRefGoogle Scholar
  58. 58.
    Ni, W. Egashira, K. Kitamoto, S. et al. (2001) New anti-monocyte chemoattractant protein-1 gene therapy attenuates atherosclerosis in apolipoprotein E-knockout mice. Circulation 103, 2096–2101.PubMedGoogle Scholar
  59. 59.
    Wrighton, C. J., HoferWarbinek, R., Moll, T., Eytner, R., Bach, F.H., and deMartin, R. (1996) Inhibition of endothelial cell activation by adenovirus- mediated expression of I kappa B alpha, an inhibitor of the transcription factor NF-kappa B. J. Exp. Med. 183(3), 1013–1022.PubMedCrossRefGoogle Scholar
  60. 60.
    Rouis, M., Adamy, C., Duverger, N., et al. (1999) Adenovirus-mediated over-expression of tissue inhibitor of metalloproteinase-1 reduces atherosclerotic lesions in apolipoprotein E-deficient mice. Circulation 100(5), 533–540.PubMedGoogle Scholar
  61. 61.
    Grossman, M., Rader, D. J., Muller, D. W. M., et al. (1995) A pilot-study of ex-vivo gene-therapy for homozygous familial hypercholesterolemia. Nature Medicine 1(11), 1148–1154.PubMedCrossRefGoogle Scholar
  62. 62.
    Kozarsky, K. F., McKinley, D. R., Austin, L. L., Raper, S. E., Stratfordperricaudet, L. D., and Wilson, J. M. (1994) In-Vivo Correction of Low-Density-Lipoprotein Receptor Deficiency in the Watanabe Heritable Hyperlipidemic Rabbit with Recombinant Adeno—viruses. J. Biol. Chem. 269(18), 13,695–13,702.Google Scholar
  63. 63.
    Kozarsky, K. F., Jooss, K., Donahee, M., Strauss, J. F., and Wilson, J. M. (1996) Effective treatment of familial hypercholesterolaemia in the mouse model using adenovirus-mediated transfer of the VLDL receptor gene. Nature Genetics 13(1), 54–62.PubMedCrossRefGoogle Scholar
  64. 64.
    Rade, J. J., Schulick, A. H., Virmani, R., and Dichek, D. A. (1996) Local adenoviral-mediated expression of recombinant hirudin reduces neointima formation after arterial injury. Nat. Med. 2, 293–298.PubMedCrossRefGoogle Scholar
  65. 65.
    Zoldhelyi, P., McNatt, J., Xu, X. M., et al. (1996) Prevention of arterial thrombosis by adenovirus-mediated transfer of cyclooxygenase gene. Circulation 93, 10–17.PubMedGoogle Scholar
  66. 66.
    Waugh, J. M., Kattash, M., Li, J. J., et al. (1999) Gene therapy to promote thromboresistance: local over—expression of tissue plasminogen activator to prevent arterial thrombosis in an in vivo rabbit model. Proc. Natl. Acad. Sci. USA 96, 1065–1070.PubMedCrossRefGoogle Scholar
  67. 67.
    Nishida, T., Ueno, H., Atsuchi, N., et al. (1999) Adenovirus-mediated local expression of human tissue factor pathway inhibitor eliminates shear stress-induced redurrent thrombosis in the injured carotid artery of the rabbit. Circ. Res. 84, 1446–1452.PubMedGoogle Scholar
  68. 68.
    Atsuchi, N., Nishida, T., Marutsuka, K., et al. (2001) Combination of a brief irrigation with tissue factor pathway inhibitor (TFPI) and adenovirus-mediated local TFPI gene transfer additively reduces neointima formation in balloon-injured rabbit carotid arteries. Circulation 103, 570–575.PubMedGoogle Scholar
  69. 69.
    Lafont, A., Durand, E., Vilde, F., et al. (1998) Thrombus generation after adenovirus-mediated gene transfer into atherosclerotic arteries. Hum. Gene Ther. 9(18), 2795–2800.PubMedGoogle Scholar
  70. 70.
    Flugelman, M. Y., Virmani, R., Leon, M. B., Bowman, R. L., and Dichek, D. A. (1992) Genetically engineered endothelial cells remain adherent and viable after stent deployment and exposure to flow in vitro. Circ. Res. 70, 348–354.PubMedGoogle Scholar
  71. 71.
    Dichek, D. A., Anderson, J., Kelly, A. B., Hanson, S. R., and Harker, L. A. (1996) Enhanced in vivo anti—thrombotic effects of endothelial cells expressing recombinant plasminogen activators transduced with retroviral vectors. Circulation 93, 301–309.PubMedGoogle Scholar
  72. 72.
    Emanueli, C. and Madeddu, P. (2001) Angiogenesis gene therapy to rescue ischaemic tissues: achievements and furture directions. Br. J. Pharm. 133, 951–958.CrossRefGoogle Scholar
  73. 73.
    Takeshita, S, Pu, LQ, Stein, LA, et al. (1994) Intramuscular Administration of Vascular Endothelial Growth- Factor Induces Dose-Dependent Collateral Artery Augmentation in a Rabbit Model of Chronic Limb Ischemia. Circulation 90(5), 228–234.Google Scholar
  74. 74.
    Takeshita, S., Isshiki, T., Mori, H., et al. (1997) Microangiographic assessment of collateral vessel formation following direct gene transfer of vascular endothelial growth factor in rats. Cardiovasc. Res. 35(3), 547–552.PubMedCrossRefGoogle Scholar
  75. 75.
    Tabata, H., Silver, M., and Isner, J. M. Arterial gene transfer of acidic fibroblast growth factor for therapeutic angiogenesis in vivo: Critical role of secretion signal in use of naked DNA. Cardiovasc. Res. 35, 470–479.Google Scholar
  76. 76.
    Isner, J. M., Pieczek, A., Schainfeld, R., et al. (1996) Clinical evidence of angiogenesis after arterial gene transfer of phVEGF(165) in patient with ischaemic limb. Lancet 348(9024), 370–374.PubMedCrossRefGoogle Scholar
  77. 77.
    Baumgartner, I., Pieczek, A., Manor, O., et al. (1998) Constitutive expression of phVEGF(165) after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 97(12), 1114–1123.PubMedGoogle Scholar
  78. 78.
    Losordo, D.W., Vale, P.R., Symes, J.F., et al. (1998) Gene therapy for myocardial angiogenesis—Initial clinical results with direct myocardial injection of phVEGF(165) as sole therapy for myocardial ischemia. Circulation 98(25), 2800–2804.PubMedGoogle Scholar
  79. 79.
    Rosengart, T. K., Lee, L. Y., Patel, S. R., et al. (1999) 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 100(5), 468–474.PubMedGoogle Scholar
  80. 80.
    Hendel, R. C., Vale, P. R., Losordo, D. W., et al. (2000) The effects of VEGF-2 gene therapy on rest and stress myocardial perfusion: Results of serial SPECT imaging. Circulation 102(18), 3716.Google Scholar
  81. 81.
    Steg, P. G., Tahlil, O., Aubailly, N., et al. (1997) Reduction of restenosis after angioplasty in an atheromatous rabbit model by suicide gene therapy. Circulation 96, 408–411.PubMedGoogle Scholar
  82. 82.
    Chang, M. W., Barr, E., Seltzer, J., et al. (1995) Cytostatic gene-therapy for vascular proliferative disorders with a constitutively active form of the retinoblastoma gene- product. Science 267(5197), 518–522.PubMedCrossRefGoogle Scholar
  83. 83.
    Chang, M. W., Barr, E., Lu, M. M., Barton, K., and Leiden, J. M. (1995) Adenovirus-mediated overexpression of the cyclin cyclin-dependent kinase inhibitor, p21 inhibits vascular smooth muscle cell proliferation and neointima formation in the rat carotid artery model of balloon angioplasty. J. Clin. Invest. 96(5), 2260–2268.PubMedGoogle Scholar
  84. 84.
    Ueno, H., Yamamoto, H., Ito, S. I., Li, J. J., and Takeshita, A. (1997) Adenovirus-mediated transfer of a dominant-negative H-ras suppresses neointimal formation in balloon-injured arteries in vivo. Arterioscler. Thromb. Vasc. Biol. 17(5), 898–904.PubMedGoogle Scholar
  85. 85.
    Ribault, S., Neuville, P., Mechine-Neuville, A., et al. (2001) Chimeric smooth muscle-specific enhancer/promoters — Valuable tools for adenovirus-mediated cardiovascular gene therapy. Circ. Res. 88(5), 468–475.PubMedGoogle Scholar
  86. 86.
    George, S. J., Capogrossi, M. C., Angelini, G. D., and Baker, A. H. (2001) Wild type p53 gene transfer inhibits neointima formation in human saphenous vein by modulation of smooth muscle cell migration and induction of apoptosis. Gene Therapy 8, 668–676.PubMedCrossRefGoogle Scholar
  87. 87.
    Chen, L. Daum, G. Forough, R. Clowes, M. Walter, U. and Clowes, A. W. (1998) Overexpression of human endothelial nitric oxide synthase in rat vascular smooth muscle cells and in balloon-injured carotid artery. Circ. Res. 82, 862–870.PubMedGoogle Scholar
  88. 88.
    Newby, A. C. and George, S. J. (1993) Proposed roles for growth factors in mediating smooth muscle proliferation in vascular pathologies. Cardiovasc. Res. 27, 1173–1183.PubMedGoogle Scholar
  89. 89.
    Yamamoto, K., Morishita, R., Tomita, N., et al. (2000) Ribozyme oligonucleotides against transforming growth factor-b inhibited neointimal formation after vascular injury in rat model. Potential application of ribozyme strategy to treat cardiovascular disease. Circulation 102, 1308–1314.PubMedGoogle Scholar
  90. 90.
    Hoffmann, R. and Mintz, G. S. (2000) Coronary instent restenosis — predictors, treatment and prevention. Eur. Heart. J. 21(21), 1739–1749.PubMedCrossRefGoogle Scholar
  91. 91.
    Varenne, O., Pislaru, S., Gillijns, H., et al. (1998) Local adenovirus-mediated transfer of human endothelial nitric oxide synthase reduces luminal narrowing after coronary angioplasty in pigs. Circulation 98(9), 919–926.PubMedGoogle Scholar
  92. 92.
    Tio, R. A., Scheuermann, T. H., Lebherz, C., et al. (1998) Adenovirus-mediated GAX gene transfer reduces in-stent restenosis in pig coronary arteries. Circulation 98(17), 3548.Google Scholar
  93. 93.
    Frimerman, A., Welch, P. J., Jin, X. M., et al. (1999) Chimeric DNA-RNA hammerhead ribozyme to proliferating cell nuclear antigen reduces stent-induced stenosis in a porcine coronary model. Circulation 99(5), 697–703.PubMedGoogle Scholar
  94. 94.
    Mann, M. J., Whittemore, A. D., Donaldson, M. C., et al. (1999) Ex-vivo gene therapy of human vascular bypass grafts with E2F decoy: the PREVENT single-centre, randomised, controlled trial. Lancet 354, 1493–1498.PubMedCrossRefGoogle Scholar
  95. 95.
    George, S. J. (1998) Tissue inhibitors of metalloproteinases and metalloproteinases in atherosclerosis. Curr. Opin. Lipidol. 9, 413–423.PubMedCrossRefGoogle Scholar
  96. 96.
    Dollery, C. M., Humphries, S. E., McClelland, A., Latchman, D. S., and McEwan, J. R. (1999) Expression of tissue inhibitor of matrix metalloproteinases 1 by use of an adenoviral vector inhibits smooth muscle cell migration and reduces neointimal hyperplasia in the rat model of vascular ballon injury. Circulation 99(24), 3199–3205.PubMedGoogle Scholar
  97. 97.
    Cheng, L., Mantile, G., Pauly, R., et al. (1998) Adenovirus-mediated gene transfer of the human tissue inhibitor of metalloproteinase-2 blocks vascular smooth muscle cell invasiveness in vitro and modulates neointimal development in vivo. Circulation 98(20), 2195–2201.PubMedGoogle Scholar
  98. 98.
    Hu, Y., Baker, A. H., Zou, Y., Newby, A. C., and Xu, Q. (2001) Local gene transfer of tissue inhibitor of metalloproteinase-2 influences vein graft remodeling in a mouse model. Arterioscler. Thromb. Vasc. Biol. 21, 1275–1280.PubMedCrossRefGoogle Scholar
  99. 99.
    Forough, R., Koyama, N., Hasenstab, D., et al. (1996) Overexpression of tissue inhibitor of matrix metalloproteinase-1 inhibits vascular smooth muscle cell functions in vitro and in vivo. Circ. Res. 79, 812–820.PubMedGoogle Scholar
  100. 100.
    Laitinen, M., Zachary, I., Breier, G., et al. (1997) VEGF gene transfer reduces intimal thickening via increased production of nitric oxide in carotid arteries. Hum. Gene Ther. 8, 1737–1744.PubMedCrossRefGoogle Scholar
  101. 101.
    Nicklin, S. A., Reynolds, P. N., Brosnan, M. J., et al. (2001) Analysis of cell-specific promoters for viral gene therapy targeted at the vascular endothelium. Hypertension 38(1), 65–70.PubMedGoogle Scholar
  102. 102.
    Symes, J. F., Losordo, D. W., Vale, P. R., et al. (1999) Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease. Ann. Thor. Surg. 68(3), 830–836.CrossRefGoogle Scholar
  103. 103.
    Laitinen, M., Hartikainen, J., Hiltunen, M. O., et al. (2000) Catheter-mediated vascular endothelial growth factor gene transfer to human coronary arteries after angioplasty. Hum. Gene Ther. 11(2), 263–270.PubMedCrossRefGoogle Scholar
  104. 104.
    Yla-Herttuala, S., Laitinen, M., Hartikainen, J., et al. (2000) Safety of VEGF gene therapy with adenovirus and plasmid/liposome vectors in coronary and peripheral vascular disease patients. Circulation 102(18), 34.Google Scholar

Copyright information

© Humana Press Inc. 2002

Authors and Affiliations

  • Sarah J. George
    • 1
  • Andrew H. Baker
  1. 1.Bristol Heart Institute, Level 7Bristol Royal InfirmaryBristolUK

Personalised recommendations