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Hypertension pp 299–314Cite as

Gene Transfer in Endothelial Dysfunction and Hypertension

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Part of the book series: Methods In Molecular Medicine™ ((MIMM,volume 108))

Abstract

Gene transfer represents a method for treatment of several cardiovascular disorders, including endothelial dysfunction and hypertension. For effective and safe gene therapy in vascular disease, a suitable therapeutic gene needs to be identified and delivered to the vasculature by appropriate delivery devices. In this chapter, we review the different vectors used, both viral and nonviral, suitable genes identified, and associated delivery devices. Several genes have been identified with a view to improve endothelial dysfunction, and we have elaborated the advantages and disadvantages of these approaches. Strategies to treat hypertension, both systemic and pulmonary, have also been described. The optimal vector has not yet been discovered although a wide variety of choices is available, each with properties that may render it suitable for specific applications. The individual characteristics of these vectors are described in relation to the proposed therapeutic paradigm. Although there are several unanswered questions in this arena, the future application of gene transfer technology to diseases of the vasculature holds significant promise.

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References

  1. Nabel, E. G., Plautz, G., Nabel, G. J., et al. (1990) Site-specific gene expression in vivo by direct gene transfer into the arterial wall. Science 249,1285–1288.

    Article  PubMed  CAS  Google Scholar 

  2. Yla-Herttuala, S. and Martin, J. F. (2000) Cardiovascular gene therapy. Lancet 355, 213–222.

    Article  PubMed  CAS  Google Scholar 

  3. Takeshita, S., Losordo, D. W., Isner, J. M., et al. (1994) Time course of recombinant protein secretion after liposome-mediated gene transfer in a rabbit arterial organ culture model. Lab. Invest. 71, 387–391.

    PubMed  CAS  Google Scholar 

  4. Turunen, M. P., Urtti, A., Yla-Herttuala, S., et al. (1999) Efficient adventitial gene delivery to rabbit carotid artery with cationic polymer-plasmid complexes. Gene Ther. 6, 6–11.

    Article  PubMed  CAS  Google Scholar 

  5. Lampela, P., Yla-Herttuala, S., Raasmaja, A., et al. (2002) The use of low-molecular-weight PEIs as gene carriers in the monkey fibroblastoma and rabbit smooth muscle cell cultures. J. Gene Med. 4, 205–214.

    Article  PubMed  Google Scholar 

  6. Young, J. L., Benoit, J. N., Dean, D. A., et al. (2003) Effect of a DNA nuclear targeting sequence on gene transfer and expression of plasmids in the intact vas-culature. Gene Ther. 10,1465–1470.

    Article  PubMed  CAS  Google Scholar 

  7. Hart, S. L., and Coutelle, C. (1995) Gene delivery and expression mediated by an integrin-binding peptide. Gene Ther. 2, 552–554.

    PubMed  CAS  Google Scholar 

  8. Harbottle, R. P., Miller, A. D., Coutelle, C., et al. (1998) An RGD-oligolysine peptide: a prototype construct for integrin-mediated gene delivery. Hum. Gene Ther. 9(7), 1037–1047.

    Article  PubMed  CAS  Google Scholar 

  9. Huber, P. E., Dzau, V. J., Hynynen, K., et al. (2003) Focused ultrasound (HIFU) induces localized enhancement of reporter gene expression in rabbit carotid artery. Gene Ther. 10,1600–1607.

    Article  PubMed  CAS  Google Scholar 

  10. Hood, J. D. and Cheresh, D. A. (2002) Targeted delivery of mutant Raf-kinase to new vessels causes tumour regression. Cold Spring Harb. Symp. Quant. Biol. 67, 285–291.

    Article  PubMed  CAS  Google Scholar 

  11. Clowes, M. M., Lynch C. M., Clowes, A. W., et al. (1994) Long-term biological response of injured rat carotid artery seeded with smooth muscle cells expressing retrovirally introduced human genes. J. Clin. Invest. 93, 644–651.

    Article  PubMed  CAS  Google Scholar 

  12. Chen, L., Walter, U., Clowes, A. W., et al. (1998) Over expression of human endothelial nitric oxide synthase in rat vascular smooth muscle cells and in bal-loon-injured carotid artery. Circ. Res. 82, 862–870.

    PubMed  CAS  Google Scholar 

  13. Griese, D. P., Weil, J., Riegger, G. A., et al. (2003) Vascular gene delivery of anticoagulants by transplantation of retrovirally-transduced endothelial progenitor cells. Cardiovasc. Res. 58, 469–477.

    Article  PubMed  CAS  Google Scholar 

  14. Marshall, E. (2003) Gene therapy. Second child in French trial is found to have leukaemia. Science 299, 320.

    Article  PubMed  CAS  Google Scholar 

  15. Naldini, L., Trono, D., Verma, I. M., et al. (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, 11382–11388.

    Article  PubMed  CAS  Google Scholar 

  16. Kay, M. A., Glorioso, J. C., Naldini, L., et al. (2001) Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. Nat. Med. 7,33–40.

    Article  PubMed  CAS  Google Scholar 

  17. Georg and Bake (2002) Gene transfer to the vasculature. Mol. Biotechnol. 22, 153–164.

    Article  Google Scholar 

  18. Lee, R. J., Springer, M. L., Blanco-Bose, W. E., et al. (2000) VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation 102, 898–901.

    PubMed  CAS  Google Scholar 

  19. Dishart, K. L., Denby, L., Baker, A. H., et al. (2003) Third-generation lentivirus vectors efficiently transduce and phenotypically modify vascular cells: implications for gene therapy. J. Mol. Cell. Cardiol. 35, 739–748.

    Article  PubMed  CAS  Google Scholar 

  20. Pfeifer, A., Cheresh, D. A., Verma, I. M., et al. (2000) Suppression of angiogen-esis by lentiviral delivery of PEX, a noncatalytic fragment of matrix metalloproteinase 2. Proc. Natl. Acad. Sci. USA 97, 12227–12232.

    Article  PubMed  CAS  Google Scholar 

  21. 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 

  22. Bett, A. J., Haddara, W., Prevec, L., et al. (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.

    Article  PubMed  CAS  Google Scholar 

  23. Hedman, M. and Yla-Herttuala, S. (2000) Gene therapy for treatment of peripheral vascular disease and coronary artery disease. Drugs Today 36, 609–617.

    PubMed  CAS  Google Scholar 

  24. 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, 2955–2965.

    Article  PubMed  CAS  Google Scholar 

  25. Wen, S., Schneider, D. B., Dichek, D. A., et al. (2000) Second generation adenoviral vectors do not prevent rapid loss of transgene expression and vector DNA from the arterial wall. Arterio Thromb. Vasc. Biol. 20,1452–1458.

    CAS  Google Scholar 

  26. Wilson, J. M. (1996) Adenoviruses as gene-delivery vehicles. N. Engl. J. Med. 334,1185–1187.

    Article  PubMed  CAS  Google Scholar 

  27. Monahan, P. E. and Samulski, R. J. (2000) Adeno-associated virus vectors for gene therapy: more pros than cons? Mol. Med. Today 6,433–440.

    Article  PubMed  CAS  Google Scholar 

  28. 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, 7951–7959.

    PubMed  CAS  Google Scholar 

  29. Wagner, J. A., Messner, A. H., Moran, M. L., et al. (1999) Safety and biological efficacy of an adenoassociated virus vector-cystic fibrosis transmembrane regulator (AAV-CFTR) in the cystic fibrosis maxillary sinus. Laryngoscope 109, 266–274.

    Article  PubMed  CAS  Google Scholar 

  30. Stedman, H., Wilson, J. M., Mendell, J., et al. Phase I clinical trial utilizing gene therapy for limb girdle muscular dystrophy: a-, b-, g, or f-sarcoglycan gene delivered with intramuscular instillations of adeno-associated vectors. Hum. Gene Ther. 11, 777–790.

    Google Scholar 

  31. Rabinowitz, J. and Samulski, R. J. (1998) Adeno-associated virus expression sys-tems for gene transfer. Curr. Opin. Biotechnol. 9,470–475.

    Article  PubMed  CAS  Google Scholar 

  32. Huttner, N. A., Girod, A., Hallek, M., et al. (2003) Analysis of site-specific transgene integration following cotransduction with recombinant AAV and a rep encoding plasmid. J. Gene Med. 5,120–129.

    Article  PubMed  CAS  Google Scholar 

  33. Gao, G. P., Alvira, M. R., Wilson, J., et al. (2002) Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc. Natl. Acad. Sci. USA 99, 11854–11859.

    Article  PubMed  CAS  Google Scholar 

  34. Walters, R. W., Chiorini, J. A., Zabner, J., et al. (2001) Binding of adeno-associated virus type 5 to 2, 3-linked sialic acid is required for gene transfer. J. Biol. Chem. 276, 20610–20616.

    Article  PubMed  CAS  Google Scholar 

  35. Girod, A. (1999) Genetic capsid modifications allow efficient re-targeting of adeno-associated virus type 2, (published erratum appears in Nat. Med. 5,1438). Nat. Med. 5, 1052–1056.

    Article  PubMed  CAS  Google Scholar 

  36. Shi, W. and Bartlett, J. S. (2003) RGD Inclusion in VP3 provides adeno-associated virus type 2 (AAV2)-based vectors with a heparan sulfate-independent cell entry mechanism. Mol. Ther. 7, 515–525.

    Article  PubMed  CAS  Google Scholar 

  37. Folliot, S., Briot, D., Rolling, F., et al. (2003) Sustained tetracycline-regulated transgene expression in vivo in rat retinal ganglion cells using a single type 2 adeno-associated viral vector. J. Gene Med. 5,493–501.

    Article  PubMed  CAS  Google Scholar 

  38. Rivera, V. M., Wilson, J., Gilman, M., et al. (1999) Long-term regulated expression of growth hormone in mice after intramuscular gene transfer. Proc. Natl. Acad. Sci. USA 96, 8657–8662.

    Article  PubMed  CAS  Google Scholar 

  39. Lynch, C. M., Hara, P. S., Geary, R. L., et al., (1997) AAV vectors for vascular gene delivery. Circulat. Res. 80,497–505.

    PubMed  CAS  Google Scholar 

  40. Maeda, Y., Ikeda, U., Ozawa, K., et al. (1997) Gene transfer into vascular cells using AAV vectors. Cardiovasc. Res. 35, 514–521.

    Article  PubMed  CAS  Google Scholar 

  41. Pajusola, K., Seppo, Y., Beuler, H., et al. (2002) Cell-type-specific characteristics modulate the transduction efficiency of AAV type 2 and restrain infection of endothelial cells. J. Virol. 76, 11530–11540.

    Article  PubMed  CAS  Google Scholar 

  42. Richter, M., Halbert, C. L., Allen, M. D., et al. (2000). Adeno-associated virus vector transduction of vascular smooth muscle cells in vivo. Physiol. Genom. 2, 117–127.

    CAS  Google Scholar 

  43. Sen, S., Bartlett, J. S., O’Brien, T., et al. (2003) Effect of adeno-associated virus (AAV) serotype on vascular gene delivery in-vivo. Circulation 108, Suppl. 4.

    Google Scholar 

  44. Sen, S. and O’Brien, T. (2003) Improving endothelial function. Irish Med. News May (2), 40–42.

    Google Scholar 

  45. Cable, D. G., O’Brien, T., Pompili, V. J., et al. (1997) Recombinant endothelial nitric oxide synthase-transduced human saphenous veins: gene therapy to augment nitric oxide production in bypass conduits. Circulation 96 (Suppl.), II-173–II-178.

    Google Scholar 

  46. Mozes, G., Katusic, Z. S., O’Brien, T., et al. (1998) Ex vivo gene transfer of endothelial nitric oxide synthase to atherosclerotic rabbit aortic rings improves relaxations to acetylcholine. Atherosclerosis 141, 265–271.

    Article  PubMed  CAS  Google Scholar 

  47. Alexander, M. Y., O’Brien, T., Dominiczak, A. F., et al. (1999) Gene transfer of endothelial nitric oxide synthase improves nitric-oxide dependent endothelial function in a hypertensive rat model. Cardiovasc. Res. 43, 798–807.

    Article  PubMed  CAS  Google Scholar 

  48. Zanetti, M., Katusic, Z., O’Brien, T., et al. (2000) Gene transfer of endothelial nitric oxide synthase improves endothelium-dependent relaxations in aorta from diabetic rabbits. Diabetologia 43, 340–347.

    Article  PubMed  CAS  Google Scholar 

  49. Sato, J., Katusic, Z. S., O’Brien, T. et al. (2000) In vivo gene transfer of endothe-lial nitric oxide synthase to carotid arteries from hypercholesterolemic rabbits enhances endothelium-dependent relaxations. Stroke 31, 968–975.

    PubMed  CAS  Google Scholar 

  50. Khurana, V. G., O’Brien, T., Katusic, Z. S., et al. (2002) Protective vasomotor effects of in vivo recombinant endothelial nitric oxide synthase gene expression in a canine model of cerebral vasospasm. Stroke 33, 782–789.

    Article  PubMed  CAS  Google Scholar 

  51. Channon, K. M., Qian, H., Neplioueva, V., et al. (1998) In vivo gene transfer of nitric oxide synthase enhances vasomotor function in carotid arteries from normal and cholesterol fed rabbits. Circulation 98,1905–1911.

    PubMed  CAS  Google Scholar 

  52. Kullo, I. J., Simari, R. D., Schwartz, R. S., et al. (1999) Vascular gene transfer. From bench to bedside. Arterioscler. Thromb. Vasc. Biol. 19, 196–207.

    PubMed  CAS  Google Scholar 

  53. Zanetti, M., Katusic, Z. S., O’Brien, T., et al. (2001) Gene transfer of superoxide dismutase isoforms reverses endothelial dysfunction in diabetic rabbit aorta. Am. J. Physiol. Heart Circ. Physiol. 280, H2516–H2523.

    PubMed  CAS  Google Scholar 

  54. Zanetti, M., Katusic, Z. S., O’Brien, T., et al. (2001) Gene transfer of manganese superoxide dismutase reverses vascular dysfunction in the absence but not in the presence of atherosclerotic plaque. Hum. Gene Ther. 12,1407–1416.

    Article  PubMed  CAS  Google Scholar 

  55. Fennell, J. P., Heistad, D., Baker, A. H., et al. (2002) Adenovirus-mediated overexpression of extracellular superoxide dismutase improves endothelial dysfunction in a rat model of hypertension. Gene Ther. 9, 110–117.

    Article  PubMed  CAS  Google Scholar 

  56. Zheng, J. S., Kovesdi, I., Chen, A. F., et al. (2003) Gene transfer of human gua-nosine 5′ triphosphate cyclohydrolase I restores vascular tetrahydrobiopterin level and endothelial function in low renin hypertension. Circulation 108,1238–1245.

    Article  PubMed  CAS  Google Scholar 

  57. Lin, K. F., Chao, J., and Chao, L. (1995) Human atrial natriuretic peptide gene delivery reduces blood pressure in hypertensive rats. Hypertension 26, 847–853.

    PubMed  CAS  Google Scholar 

  58. Lin, K. F., Chao, L., and Chao, J. (1997) Prolonged reduction of high blood pressure with human nitric oxide synthase gene delivery. Hypertension 30 (3 Pt 1), 307–313.

    PubMed  CAS  Google Scholar 

  59. Chao, J., Jin, L., Chao L., et al. (1997) Adrenomedullin gene delivery reduces blood pressure in spontaneously hypertensive rats. Hypertens. Res. 20, 269–277. Errata: Hypertens. Res. 22, 229 (1999); Hypertens. Res. 24, 611 (2001).

    Article  PubMed  CAS  Google Scholar 

  60. Lin, K. F., Chao, L., and Chao, J. (1998) Atrial natriuretic peptide gene delivery attenuates hypertension, cardiac hypertrophy, and renal injury in salt-sensitive rats. Hum. Gene Ther. 9, 1429–1438. Errata: Hum. Gene Ther. 12, 2034 (2001).

    Article  Google Scholar 

  61. Dobrzynski, E., Chao, J., Chao, L., et al. (1999) Adenovirus-mediated Kallikrein gene delivery attenuates hypertension and protects against renal injury in deoxy-corticosterone-salt rats. Immuno-Phamacology 44, 57–65.

    CAS  Google Scholar 

  62. Gardon, M. L., Katovich, M. J., Raizada, M. K., et al. (1999) The potential use of gene therapy in the control of hypertension. Drugs Today 35, 925–930.

    PubMed  CAS  Google Scholar 

  63. Nakazono, K., Watanabe, N., Matsuno, K., Sasaki, J., Sato, T., Inoue, M. (1991) Does superoxide underlie the pathogenesis of hypertension? Proc. Natl. Acad. Sci. USA 88, 10045–10048.

    Article  PubMed  CAS  Google Scholar 

  64. Chu, Y., Iida, S., Heistad, D. D., et al. (2003) Gene transfer of extracellular super-oxide dismutase reduces arterial pressure in spontaneously hypertensive rats: role of heparin-binding domain. Circ. Res. 92,461–468.

    Article  PubMed  CAS  Google Scholar 

  65. Engelhardt, J. F., Heistad, D. D., Chen, A. F., et al. (2003) Endothelin-1 stimulates arterial VCAM-1 expression via NADPH oxidase-derived superoxide in min-eralocorticoid hypertension. Hypertension 42, 997–1003.

    Article  PubMed  Google Scholar 

  66. Tummala, P. E., Chen, X. L., Sundell, C. L., et al. (1999) Angiotensin II induces vascular cell adhesion molecule-1 expression in rat vasculature: a potential link between the renin-angiotensin system and atherosclerosis. Circulation 100, 1223–1229.

    PubMed  CAS  Google Scholar 

  67. Li, L., Crockett, E., Wang, D. H., Galligan, J. J., Fink, G. D., and Chen, A. F. (2002) Gene transfer of endothelial NO synthase and manganese superoxide dismutase on arterial vascular cell adhesion molecule-1 expression and superoxide production in deoxycorticosterone acetate-salt hypertension. Arterioscler. Thromb. Vasc. Biol. 22, 249–255.

    Article  PubMed  CAS  Google Scholar 

  68. Abraham, N. G. (2003) Therapeutic applications of human heme oxygenase gene transfer and gene therapy. Curr. Pharm. Des. 9, 2513–2524.

    Article  PubMed  CAS  Google Scholar 

  69. Reaves, P. Y., Katovich, M. J., Raizada, M. K., et al. (1999) Permanent cardiovascular protection from hypertension by the AT(1) receptor antisense gene therapy in hypertensive rat offspring. Circ. Res. 85, e44–e50.

    PubMed  CAS  Google Scholar 

  70. Zhang, Y. C., Shen, L., Phillips, M. I., et al. (2000) Antisense inhibition ofβ1 adrenergic receptor mRNA in a single dose produces a profound and prolonged reduction in high blood pressure in spontaneously hypertensive rats. Circulation 101, 682–688.

    PubMed  CAS  Google Scholar 

  71. Giaid, A. and Saleh, D. (1995) Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N. Engl. J. Med. 333,214–221.

    Article  PubMed  CAS  Google Scholar 

  72. Champion, H. C., Bivalacqua, T. J., Kadowitz, P. J., et al. (2002) Adenoviral gene transfer of endothelial nitric-oxide synthase (eNOS) partially restores normal pulmonary arterial pressure in eNOS-deficient mice. PNAS 99, 13248–13253.

    Article  PubMed  CAS  Google Scholar 

  73. Champion, H. C., Heistad D. T. J., Kadowitz, P. J., et al. (2000) In vivo gene transfer of prepro-calcitonin gene-related peptide to the lung attenuates chronic hypoxia-induced pulmonary hypertension in mouse. Circulation 101, 923–930.

    PubMed  CAS  Google Scholar 

  74. Ikeda, Y., Yonemitsu, Y., Sueishi, K., et al. (2002) Anti-monocyte chemoattrac-tant protein-1 gene therapy attenuates pulmonary hypertension in rats. Am. J. Physiol. Heart Circ. Physiol. 283, H2021–H2028.

    PubMed  CAS  Google Scholar 

  75. Zhao, Y. D., Ng, D., Stewart, D. J., et al. (2003) Protective role of angiopoietin-1 in experimental pulmonary hypertension. Circ. Res. 92, 984–991.

    Article  PubMed  CAS  Google Scholar 

  76. Bledsoe, G., Chao, L., and Chao, J. (2003) Kallikrein gene delivery attenuates cardiac remodeling and promotes neovascularization in spontaneously hypertensive rats. Am. J. Physiol. Heart Circ. Physiol. 285, H1479–H1488.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, St. Elizabeth’s Medical Center, Boston, MA

    Sabyasachi Sen

  2. Department of Medicine, Clinical Science Institute, University College Hospital, Galway, Ireland

    Padraig M. Strappe

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  1. Sabyasachi Sen
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  2. Padraig M. Strappe
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  3. Timothy O’Brien
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Editors and Affiliations

  1. Moyne Institute for Preventive Medicine, Trinity College, Dublin, Ireland

    Jérôme P. Fennell

  2. Division of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK

    Andrew H. Baker

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Sen, S., Strappe, P.M., O’Brien, T. (2005). Gene Transfer in Endothelial Dysfunction and Hypertension. In: Fennell, J.P., Baker, A.H. (eds) Hypertension. Methods In Molecular Medicine™, vol 108. Humana Press. https://doi.org/10.1385/1-59259-850-1:299

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  • DOI: https://doi.org/10.1385/1-59259-850-1:299

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-323-7

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