Dose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type I: Implications for clinical trials

Vincent Lambert, Carine Munaut, Peter Carmeliet, Robert D. Gerard, Paul J. Declerck, Ann Gils, Carel Claes, Jean Michel Foidart, Agnès Noël, Jean Marie Rakic

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41 Scopus citations

Abstract

PURPOSE. To explain the conflicting reports about the influence of plasminogen activator inhibitor type (PAI-1) on pathologic angiogenesis, such as occurs during the exudative form of age-related macular degeneration. METHODS. The expression of PAI-1 mRNA was analyzed in human and murine choroidal neovascularization (CNV) by RT-PCR. The influences of increasing doses of recombinant PAI-1 were evaluated by daily intraperitoneal injections in PAI-1-/- and wild-type animals with a model of laser-induced CNV. The double mechanism of action of PAI-1 (proteolytic activity inhibition versus vitronectin binding) was explored by immunohistochemical localization of fibrinogen/fibrin and by injection of recombinant PAI-1 protein defective for vitronectin binding or with adenoviral vectors bearing a mutated binding-deficient PAI-1 gene. RESULTS. PAI-1 expression was present in human CNV and strongly induced in the course of experimental subretinal neovascularization. Daily injections of recombinant PAI-1 proteins in control and PAI-1-/- animals demonstrated that PAI-1 could exhibit both pro- and antiangiogenic effects, dependent on the dose. PAI-1 mutants defective for vitronectin binding were used to show that PAI-1 promotes choroidal pathologic angiogenesis merely through its antiproteolytic activity. CONCLUSIONS. These observations may help to reconcile reports with opposite results regarding the effects of PAI-1 on angiogenesis and certainly warn against uncontrolled use of PAI-1-modulating drugs in clinical trials.

Original languageEnglish (US)
Pages (from-to)2791-2797
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume44
Issue number6
DOIs
StatePublished - Jun 1 2003

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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    Lambert, V., Munaut, C., Carmeliet, P., Gerard, R. D., Declerck, P. J., Gils, A., Claes, C., Foidart, J. M., Noël, A., & Rakic, J. M. (2003). Dose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type I: Implications for clinical trials. Investigative Ophthalmology and Visual Science, 44(6), 2791-2797. https://doi.org/10.1167/iovs.02-1179