May 2003
Volume 44, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2003
Severe Inhibition of Choroidal Neovascularization in Mice With a Combined Deficiency of MMP-2 and MMP-9 Genes
Author Affiliations & Notes
  • J.A. Rakic
    Ophthalmology, University Hospital (CHU), Liege, Belgium
  • V. Lambert
    Laboratory of Tumor and Development Biology, University of Liege, Liege, Belgium
  • B. Wielockx
    Department of Molecular Biology, University of Ghent, Ghent, Belgium
  • C. Munaut
    Department of Molecular Biology, University of Ghent, Ghent, Belgium
  • Z. Werb
    Department of Anatomy, University of California, San Francisco, CA, United States
  • A. Baker
    Bristol Heart Institute, University of Bristol, Bristol, United Kingdom
  • A. Noel
    Bristol Heart Institute, University of Bristol, Bristol, United Kingdom
  • J. Foidart
    Bristol Heart Institute, University of Bristol, Bristol, United Kingdom
  • Footnotes
    Commercial Relationships  J.A. Rakic, None; V. Lambert, None; B. Wielockx, None; C. Munaut, None; Z. Werb, None; A. Baker, None; A. Noel, None; J. Foidart, None.
  • Footnotes
    Support  Les Amis des Aveugles, Ghlin; FRSM
Investigative Ophthalmology & Visual Science May 2003, Vol.44, 3938. doi:
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      J.A. Rakic, V. Lambert, B. Wielockx, C. Munaut, Z. Werb, A. Baker, A. Noel, J. Foidart; Severe Inhibition of Choroidal Neovascularization in Mice With a Combined Deficiency of MMP-2 and MMP-9 Genes . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3938.

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Abstract

Abstract: : Purpose: To evaluate the relative contribution of matrix metalloproteinases (MMPs) 2, 9 and MT1-MMP to choroidal neovascularization (CNV) such as occurring during the exudative form of age-related macular degeneration (AMD). Methods: The expression profile of different MMPs was evaluated in human and experimental choroidal neovascularization by RT-PCR. The activity of MMP-2 and MMP-9 was studied by gelatin and in situ zymography. The influence of endogenous MMP-9 and MMP-2 was explored in single (MMP-9 KO, MMP-2 KO) or double gene (MMP-2,9 KO) deficient mice with a model of laser-induced CNV. To investigate the therapeutical potential of endogenous or pharmacological MMP inhibition, the observations were extended to wild-type (WT) mice treated with adenovirus-mediated TIMP-1 or TIMP-2 transfer, with a broad spectrum (BB-94) or a selective synthetic MMP-inhibitor. Results: Both MMP-2 and MMP-9 were increasingly processed during the early stages of CNV formation, with the appearance of active forms of MMP-2 resulting from MT1-MMP overexpression. The incidence and the severity of CNV were strongly decreased in double deficient compared to single gene deficient mice or corresponding WT strains. In these MMP2,9 deficient mice, the reduced neovascularization was accompanied by fibrinogen/fibrin accumulation. Treatment of WT mice with overexpression of endogenous inhibitor TIMP-2 (delivered by adenoviral vectors) or with daily injection of a synthetic selective MMP inhibitor significantly decreased the magnitude of the pathological reaction. Conclusions: These findings suggest that MMP-2 and MMP-9 cooperate in the development of the disease and that their selective inhibition might represent an alternative strategy for the treatment of choroidal neovascularization.

Keywords: choroid: neovascularization • proteolysis • pharmacology 
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