Reference : Dose-dependent modulation of choroidal neovascularization by plasminogen activator in...
Scientific journals : Article
Human health sciences : Ophthalmology
Dose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type 1: Implications for clinical trials
Lambert, Vincent mailto [Centre Hospitalier Universitaire de Liège - CHU > > Ophtalmologie >]
Munaut, Carine mailto [Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement >]
Carmeliet, Peter [> > > >]
Gerard, Robert D. [> > > >]
Declerck, Paul J. [> > > >]
Gils, Ann [> > > >]
Claes, Carel [> > > >]
Foidart, Jean-Michel mailto [Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique >]
Rakic, Jean-Marie mailto [Université de Liège - ULiège > Département des sciences cliniques > Ophtalmologie >]
Noël, Agnès mailto [Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme >]
Investigative Ophthalmology & Visual Science
Assoc Research Vision Ophthalmology Inc
Yes (verified by ORBi)
[en] age-related macular degeneration ; PAI-1 ; angiogenesis
[en] 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 RTPCR. The influences of increasing doses of recombinant PAI-1 were evaluated by daily intraperitoneal injections in PAI-1-1-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 PAL I modulating drugs in clinical trials.

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