Skip to main content
SpringerLink
Log in

Development Of Rat Models For Choroidal Neovascularisation (CNV)

A Comparison between Laser and Recombinant Adenovirus Induced CNV

  • Chapter
Retinal Degenerative Diseases and Experimental Therapy

  • 425 Accesses

Abstract

This project aimed to investigate whether the overexpression of vascular endothelial growth factor (VEGF) in the retinal pigment epithelium (RPE), induced by recombinant adenovirus mediated delivery of VEGF164, is sufficient to initiate the development of leaky choroidal blood vessels in a rat model. Eyes of pigmented rats were subjected to krypton laser photocoagulation or subretinal injection with recombinant adenovirus constructs Ad.RSV.VEGF or Ad.CMV.VEGF. Initially the animals were examined with fundus photography followed by fluorescein angiography. Retinal photographs demonstrated that the krypton laser produced moderate burns and that the subretinal injection resulted in the formation of a bleb in the subretinal space. Injection of control recombinant adenovirus Ad. RSV.βgal resulted in the expression of βgal reporter gene in the RPE layer. Of the 141 laser spots delivered into a total of 17 rat eyes, 52.4% developed fluorescein leakage that was detectable by angiography. Of seven eyes injected with Ad.RSV.VEGF, 5 developed leakage at 2 weeks post injection, and of 8 eyes which were injected with Ad.CMV.VEGF, 5 developed leakage at 1 week post injection. However, the development of leaky blood vessels was temporary and both Ad.RSV.VEGF and Ad.CMV.VEGF injected animals showed regression of leaky vessels by 4 and 5 weeks post injection, respectively. These results suggest that the upregulation of VEGF in the RPE layer may be a key factor in the series of events leading to the development of CNV.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. W.R. Green and D.J. Wilson, 1986, Choroidal neovascularization, Ophthalmology 93:1169–1176.

    PubMed  CAS  Google Scholar 

  2. S.H. Sarks, 1973, New vessel formation beneath the retinal pigment epithelium in senile eyes, Br J Ophthalmol 57:951–965.

    PubMed  CAS  Google Scholar 

  3. W.R. Green, C. Enger, 1993, Age-related macular degeneration histopathologic studies. The 1993 Lorenz E. Zimmerman Lecture. Ophthalmology 100:1519–1535.

    CAS  Google Scholar 

  4. N.M. Bressler, J.C. Silva, S.B. Bressler, S.L. Fine, and W.R. Green, 1994, Clinicopathologic correlation of drusen and retinal pigment epithelial abnormalities in age-related macular degeneration. Retina 14(2):130–142.

    Article  PubMed  CAS  Google Scholar 

  5. S.H. Sarks, 1976, Ageing and degeneration in the macular region: a clinico-pathological study, Br J Ophthalmol 60:324–341.

    PubMed  CAS  Google Scholar 

  6. S.H. Sarks, D. van Driel, L. Maxwell, and M.C. Killingsworth, 1980, Softening of drusen and subretinal neovascularization, Trans Ophthalmol Soc UK 100:414–422.

    PubMed  CAS  Google Scholar 

  7. W.J. Heriot, P. Henkind, R.W. Bellhorn, and M.S. Burns, 1984, Choroidal neovascularization can digest Bruch’s membrane—A prior break is not essential, Ophthalmology 91(12):1603–1608.

    PubMed  CAS  Google Scholar 

  8. A. Pollack, W.J. Heriot, and P. Henkind, 1986, Celluar processes causing defects in Bruch’s membrance following krypton laser photocoagulation, Ophthalmology 93:1113–1119.

    PubMed  CAS  Google Scholar 

  9. R.N. Frank, A. Das, and M.L. Weber, 1989, A model of subretinal neovascularization in the pigmented rat, Curr Eye Res 8:239–247.

    PubMed  CAS  Google Scholar 

  10. X Yi, N Ogata, M. Komada, K Takahashi, K. Omori,and M. Uyama, 1997, Vascular endothelial growth factor expression in choroidal neovascularization in rats. Graefe’s Arch Clin Exp Ophthalmol:313–319.

    Google Scholar 

  11. T. Ishibashi, Y. Hata, H. Yoshikawa, K. Nakagawa, K. Sueishi, and H. Inomata, 1997, Expression of vascular endothelial growth factor in experimental choroidal neovascularization. Graefe’s Arch Clin Exp Ophthalmol 235:159–167.

    Article  CAS  Google Scholar 

  12. E.T. Dobi, C.A. Puliafito, and M. Destro, 1989, A new model of experimental choroidal neovascularization in the rat, Arch Ophthalmol 107:264–269.

    PubMed  CAS  Google Scholar 

  13. L. Feeney-Burns, C. Gao, and E.R. Berman, 1988, The fate of immunoreactive opsin following phagocytosis by pigment epithelium in human and monkey retinas, Invest Ophthalmol Vis Sci 29:708–719.

    PubMed  CAS  Google Scholar 

  14. W. Shen, M. Yu, C. Barry, I.J. Constable, and P.E. Rakoczy, 1998, Expression of cell adhesion molecules and vascular endothelial growth factor in experimental choroidal neovascularisation in the rat, Br J Ophthalmol 82—in press

    Google Scholar 

  15. M.C. Killingsworth, S.H. Sarks, 1982, Giant cells in disciform macular degeneration of the human eye, Micron 13(3):359–360.

    Google Scholar 

  16. S.H. Sarks, P.L. Penfold, M.C. Killingsworth, and D. van Driel, 1985, Patterns in Macular Degeneration, in: Retinal Diseases, (S.J. Ryan, A.K. Dawson, eds.) pp. 87–93, Grune & Stratton. Inc. NY.

    Google Scholar 

  17. P.L. Penfold, M.C. Killingsworth, and S.H. Sarks, 1985, Senile macular degeneration: The involvement of immunocompetent cells, Graefe’s Arch Clin Exp Ophthalmol 223:69–76.

    Article  CAS  Google Scholar 

  18. N. Ferrara, T. Davis-Smyth, 1997, The biology of vascular endothelial growth factor, Endocr Rev 18(1):4–25.

    Article  PubMed  CAS  Google Scholar 

  19. D.W. Leung, G. Cachianes, W. Kuang, D.V. Goeddel, and N. Ferrara, 1989, Vascular endothelial growth factor is a secreted angiogenic mitogen, Science 246:1306–1309.

    Article  PubMed  CAS  Google Scholar 

  20. H.F. Dvorak, L.F. Brown, M. Detmar, and A.M. Dvorak. 1995, Vascular permeanility factor vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146:1029–1039.

    PubMed  CAS  Google Scholar 

  21. A. Minchenko, T. Bauer, S. Salceda, and J. Caro, 1994, Hypoxic stimulation of vascular endothelial growth factor expression in vitro and in vivo, Lab Invest 71:374–379.

    PubMed  CAS  Google Scholar 

  22. R.J. D’ Amato, A.P. Adamis, 1995, Angiogenesis inhibition in age-related macular degeneration, Ophthalmology 102:1261–1262.

    PubMed  Google Scholar 

  23. P.A. D’Amore, 1994, Mechanisms of Retinal and Choroidal neovascularization, Invest Ophthalmol Vis Sci 35:3974–3979.

    PubMed  CAS  Google Scholar 

  24. H.P. Heidenkummer, 1991, Age-related macular degeneration: current aspects of pathogenesis and treatment, Eye Science 7:6–20.

    PubMed  CAS  Google Scholar 

  25. P.E. Rakoczy, C.M. Lai, M. Baines, S. Di Grandi, J.H. Fitton, and I.J. Constable, 1997, Modulation of cathepsin D activity in retinal pigment epithelial cells, Biochem J 324:935–940.

    PubMed  CAS  Google Scholar 

  26. W.R. Green. 1985, Pathology of the macula, in: Ophthalmic Pathology, Volume 2 (W.H. Spencer, ed.) pp. 924–1034, W.B. Saunders Company.

    Google Scholar 

  27. S.O. Sykes, N.M. Bressler, M.G. Maguire, and A.P. Schachat, 1994, Detecting recurrent chorodial neovascularization comparison of clinical examination with and without fluorescein angiography, Arch Ophthalmol 112(12):1561–1566.

    PubMed  CAS  Google Scholar 

  28. L. da Cruz, P. Rakoczy, M. Perricaudet, and I. Constable, 1996, Dynamics of gene transfer to retinal pigment epithelium, Invest Ophthalmol Vis Sci 37(12):2447–2454.

    PubMed  Google Scholar 

  29. T.C. Becker, R.J. Noel, W.S. Coats, A.M. Gomez-Foix,T. Alam, R.D. Gerard, and C.B. Newgard, 1994, Use of recombinant adenovirus for metabolic engineering of mammalian cells, in: Methods in Cell Biology, Volume 43 pp. 161–189, Academic Press.

    Article  PubMed  CAS  Google Scholar 

  30. W. Zhang, P.E. Koch, and J.A. Roth, 1995, Detection of wild-type contamination in a recombinant adenoviral preparation by PCR, Biotechniques 18:444–446.

    PubMed  CAS  Google Scholar 

  31. A.C. Bird, N.M. Bressler, S.B. Bressler, I.H. Chisholm, G. Coscas, and M.D. David, 1995, An international classification and grading system for age-related maculopathy and age-related macular degeneration. Surv Ophthalmol 39(5):367–374.

    Article  PubMed  CAS  Google Scholar 

  32. S.J. Ryan. 1989, Subretinal neovascularization, in: Retina, (S.J. Ryan, E.J. Murray, and Patz, eds.) pp. 107–125, Mosby, St Louis.

    Google Scholar 

  33. R.N. Frank, R.H. Amin, D. Eliott, J.E. Puklin, and G.W. Abrams, 1996, Basic fibroblast growth factor and vascular endothelial growth factor are present in epiretinal and choroidal neovascular membranes, Am J Ophthalmol 122:393–403.

    PubMed  CAS  Google Scholar 

  34. R.N. Frank, 1997, Growth factors in age-related macular degeneration:pathogenic and therapeutic implications, Ophthalmic Research 29:341–353.

    Article  PubMed  CAS  Google Scholar 

  35. P.F. Lopez, B.D. Sippy, H.M. Lambert, A.B. Thach, and D.R. Hinton, 1996, 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 37:855–868.

    PubMed  CAS  Google Scholar 

  36. A. Kvanta, P.V. Algvere, L. Berglin, and S. Seregard, 1996, Subfoveal fibrovascular membranes in Age-related macular degeneration express vascular endothelial growth factor, Invest Ophthalmol Vis Sci 37(9):1929–1934.

    PubMed  CAS  Google Scholar 

  37. G.A. Lutty, D.S. McLeod, C. Merges, A. Diggs, and J. Plouet, 1996, Localization of Vascular Endothelial Growth Factor in Human Retina and Choroid, Arch Ophthalmol 114:971–977.

    PubMed  CAS  Google Scholar 

  38. N.C. Tsang, P.L. Penfold, P.J. Snitch, and F. Billson, 1992, Serum levels of antioxidants and age-related macular degeneration. Documenta Ophthalmologica 81(4):387–400.

    Article  PubMed  CAS  Google Scholar 

  39. B. Martini, S.J. Ryan, 1992, Argon laser lesion of the retina: occurrence and origin of macrophages. Euro J Ophthalmol 2:51–57.

    CAS  Google Scholar 

  40. X. Yi, K. Takahashi, N. Ogata, and M. Uyama, 1996, Immunohischemical proof of origin of macrophages in laser photocoagulation lesion in the retina. Jpn J Ophthalmol 40:192–201.

    PubMed  CAS  Google Scholar 

  41. H. Kimura, T. Sakamoto, C. Spee, and et al. 1995, A new model for experimental subretinal neovascularisation in the rabbit, Invest Ophthalmol Vis Sci 35:3429–3435.

    Google Scholar 

  42. N. Ogata, M. Matsushima, Y. Takada, T. Tobe, and et al. 1996, Expression of basic fibroblast growth factor mRNA in developing choroidal neovascularization, Curr Eye Res:1008–1018.

    Google Scholar 

  43. H.G.T. Blaauwgeers, G.M. Holtkamp, P. Koolwijk, van Hinsbergh, V.M. Kroon, A. Kijistra, and R. Schlingemann, 1998, Preferential basal secretion of VEGF by RPE in vitro and expression of its receptor KDR on the inner choriocapillaris in vitro suggest a trophic relation in the normal eye, Invest Ophthalmol Vis Sci 39(4):S372

    Google Scholar 

  44. L. da Cruz, P. Rakoczy, M, Perricaudet, and I.J. Constable, 1996, The dynamics of gene transfer to retinal pigment epithelium. Invest Opthalmol Vis Sci 37(12):2447–2454.

    Google Scholar 

  45. M.B. Reichel, R.R. Ali, A.J. Thrasher, D.M. Hunt, S.S. Bhattacharya, and D. Baker, 1998, Immune responses limit adenovirally medited gene expression in the adult mouse eye, Gene Therapy 5:1038–1046.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre for Ophthalmology and Visual Science, University of Western Australia, 2 Verdun St., Nedlands, 6009, Australia

    P. E. Rakoczy, M. Yu, M. Lai & I. J. Constable

  2. Lions Eye Institute, 2 Verdun St., Nedlands, 6009, Australia

    W. Y. Shen, K. Spilsbury & C. J. Barry

Authors
  1. P. E. Rakoczy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. Y. Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Spilsbury
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. J. Barry
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. I. J. Constable
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Cole Eye Institute, The Cleveland Clinic Foundation, Cleveland, Ohio

    Joe G. Hollyfield

  2. Dean A. McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

    Robert E. Anderson

  3. Beckman Vision Center, University of California, San Francisco, San Francisco, California

    Matthew M. LaVail

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Kluwer Academic / Plenum Publishers

About this chapter

Cite this chapter

Rakoczy, P.E. et al. (1999). Development Of Rat Models For Choroidal Neovascularisation (CNV). In: Hollyfield, J.G., Anderson, R.E., LaVail, M.M. (eds) Retinal Degenerative Diseases and Experimental Therapy. Springer, Boston, MA. https://doi.org/10.1007/978-0-585-33172-0_36

Download citation

  • DOI: https://doi.org/10.1007/978-0-585-33172-0_36

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-306-46193-4

  • Online ISBN: 978-0-585-33172-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation