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Experimental subretinal neovascularization is inhibited by adenovirus-mediated soluble VEGF/flt-1 receptor gene transfection: a role of VEGF and possible treatment for SRN in age-related macular degeneration

Gene Therapy volume 7, pages 978–985 (2000)Cite this article

Abstract

Accumulating evidence has shown the importance of vascular endothelial growth factor (VEGF) in chorioretinal angiogenesis. However, whether or not VEGF is indeed critical for the pathogenesis of subretinal neovascularization (SRN) in adulthood, which is a serious complication of age-related macular degeneration, has to be further investigated. We constructed an adenovirus expressing an entire ectodomain of the human VEGF receptor/flt-1 fused to Fc portion of human IgG (Adflt-ExR): this soluble receptor is secreted from Adflt-ExR-transfected cells. We studied the effect of Adflt-ExR on the formation of experimental SRN. Experimental SRN was induced by intense photocoagulation on the retina in pigmented rats and Adflt-ExR was injected into the femoral muscle. The formation of SRN assessed by fluorescein angiography was more significantly inhibited for 7 days in the Adflt-ExR-treated rats than in the control rats who received either an adenovirus vector encoding LacZ gene or balanced salt solution (BSS). The serum concentration of this soluble receptor increased for 7 days and thereafter gradually decreased. An immunohistochemical study disclosed the fibroblast cell proliferation and inflammatory cell infiltration to be reduced in the photocoagulation spot of Adflt-ExR-treated rats. VEGF plays a crucial role in the formation of SRN and VEGF soluble receptor gene transfection can inhibit SRN. This method will contribute to future gene therapy for age-related macular degeneration.

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References

  1. Ghafour IM, Allan D, Foulds WS . Common causes of blindness and visual handicap in the west of Scotland Br J Ophthalmol 1983 67: 209–213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ryan SJ, Stout JT, Dugel PU . Subretinal neovascularization. In: SJ Ryan (ed) The Retina vol 2: Mosby: St Louis 1994 pp 1027–1047

    Google Scholar 

  3. Kvanta A, Algvere PV, Berglin L, Seregard S . Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor Invest Ophthalmol Vis Sci 1996 37: 1929–1934

    CAS  PubMed  Google Scholar 

  4. Aiello LP et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders New Engl J Med 1994 331: 1480–1487

    Article  CAS  PubMed  Google Scholar 

  5. Lopez PF et al. Transdifferentiated retinal pigment epithelial cell are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes Invest Ophthalmol Vis Sci 1996 37: 855–868

    CAS  PubMed  Google Scholar 

  6. Ishibashi T et al. Expression of vascular endothelial growth factor in experimental choroidal neovascularization Graefe's Arch Clin Exp Ophthalmol 1997 235: 159–167

    Article  CAS  Google Scholar 

  7. Sakamoto T et al. Effect of tecogalan sodium on angiogenesis in vitro by choroidal endothelial cells Invest Ophthalmol Vis Sci 1995 36: 1076–1083

    CAS  PubMed  Google Scholar 

  8. Lopez PF et al. Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes Invest Ophthalmol Vis Sci 1996 37: 855–868

    CAS  PubMed  Google Scholar 

  9. Tobe T, Takahashi K, Ohkuma H, Uyama M . Experimental choroidal neovascularization in the rat J Jpn Ophthalmol Soc 1994 98: 837–845

    CAS  Google Scholar 

  10. Dobi TE, Puliafito AC, Dwetro M . A new model of experimental choroidal neovascularization in the rat Arch Ophthalmol 1989 107: 264–269

    Article  CAS  PubMed  Google Scholar 

  11. Frank NR, Das A, Weber ML . A model of subretinal neovascularization in the pigmented rat Curr Eye Res 1989 8: 239–247

    Article  CAS  PubMed  Google Scholar 

  12. Ferrara N et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene Nature 1996 380: 439–442

    Article  CAS  PubMed  Google Scholar 

  13. Okamoto N et al. Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization Am J Pathol 1997 151: 281–291

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Borgström P, Hillan KJ, Sriramarao P, Ferrara N . Complete inhibition of angiogenesis and growth of microtumors by anti-vascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital videomicroscopy Cancer Res 1996 56: 4032–4039

    PubMed  Google Scholar 

  15. Shibuya M et al. Possible involvement of VEGF-FLT tyrosine kinase receptor system in normal and tumor angiogenesis Princess Takamatsu Symposia 1994 24: 162–170

    CAS  PubMed  Google Scholar 

  16. Breier G, Clauss M, Risau W . Coordinate expression of vascular endothelial growth factor receptor-1 (flt-1) and its ligand suggests a paracrine regulation of murine vascular development Dev Dynam 1995 204: 228–239

    Article  CAS  Google Scholar 

  17. Takahashi T, Shibuya M . The 230kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-γ pathway and partially induces mitotic signals in NIH3T3 fibroblasts Oncogene 1997 14: 2079–2089

    Article  CAS  PubMed  Google Scholar 

  18. Aiello LP et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins Proc Natl Acad Sci USA 1995 92: 10457–10461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Anderson WF . Human gene therapy Science 1992 256: 808–813

    Article  CAS  PubMed  Google Scholar 

  20. Ogata N et al. Expression of basic fibroblast growth factor mRNA in developing choroidal neovascularization Curr Eye Res 1996 15: 1008–1018

    Article  CAS  PubMed  Google Scholar 

  21. Zhang NL, Samadani EE, Frank RN . Mitogenesis and retinal pigment epithelial cell antigen expression in the rat after krypton laser photocoagulation Invest Ophthalmol Vis Sci 1993 34: 2412–2424

    CAS  PubMed  Google Scholar 

  22. Takehana Y et al. Suppression of laser-induced choroidal neovascularization by oral tranilast in the rat Invest Ophthalmol Vis Sci 1999 40: 459–466

    CAS  PubMed  Google Scholar 

  23. Guerrin M et al. Vasculotropin/vascular endothelial growth factor is an autocrine growth factor for human retinal pigment epithelial cells cultured in vitro J Cell Physiol 1995 164: 385–394

    Article  CAS  PubMed  Google Scholar 

  24. Ferrara N et al. Vascular endothelial growth factor is essential for corpus luteum angiogenesis Nature Med 1998 4: 336–340

    Article  CAS  PubMed  Google Scholar 

  25. Sakamoto T et al. Retinal functional change caused by anadenoviral vector-mediated transfection of LacZ gene Hum GeneTher 1998 9: 789–799

    CAS  Google Scholar 

  26. Ueno H et al. Quantitative analysis of repeat adenovirus-mediated gene transfer into injured canine femoral arteries Arterioscl Thromb Vasc Biol 1995 15: 2246–2253

    Article  CAS  PubMed  Google Scholar 

  27. Fukushima M, Nakashima Y, Sueishi K . Thrombin enhances release of tissue plasminogen activator from bovine corneal endothelial cells Invest Ophthalmol Vis Sci 1989 30: 1576–1583

    CAS  PubMed  Google Scholar 

  28. Yoshimura N et al. Photocoagulated human retinal pigment epithelial cells produce an inhibitor of vascular endothelial cell proliferation Invest Ophthalmol Vis Sci 1995 36: 1686–1691

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research from Ministry of Education, Science and Culture of the Japanese Government, and by the grants from Japan National Society for the Prevention of Blindness (Tokyo, Japan), from the Fukuoka Anti-Cancer Association (Fukuoka, Japan), from Kaibara Morikazu Medical Science Promotion Foundation (Fukuoka, Japan), from the Casio Science Promotion Foundation (Tokyo, Japan), and from Takeda Medical Research Foundation, from Tokyo Biochemical Society and the Health Sciences Research Grants Japan.

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Authors and Affiliations

  1. Department of Ophthalmology, Faculty of Medicine, Kyushu University, Fukuoka, Japan

    M Honda, T Sakamoto, T Ishibashi & H Inomata

  2. Department of Molecular Cardiology, Research Institute of Angiocardiology and Cardiovascular Clinic, Faculty of Medicine, Kyushu University, Fukuoka, Japan

    H Ueno

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  1. M Honda
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  2. T Sakamoto
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  3. T Ishibashi
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Honda, M., Sakamoto, T., Ishibashi, T. et al. Experimental subretinal neovascularization is inhibited by adenovirus-mediated soluble VEGF/flt-1 receptor gene transfection: a role of VEGF and possible treatment for SRN in age-related macular degeneration. Gene Ther 7, 978–985 (2000). https://doi.org/10.1038/sj.gt.3301203

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