[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.
Disciplines :
Ophthalmology
Author, co-author :
Lambert, Vincent ; Centre Hospitalier Universitaire de Liège - CHU > Ophtalmologie
Munaut, Carine ; 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 ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique
Rakic, Jean-Marie ; Université de Liège - ULiège > Département des sciences cliniques > Ophtalmologie
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Language :
English
Title :
Dose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type 1: Implications for clinical trials
Publication date :
June 2003
Journal title :
Investigative Ophthalmology and Visual Science
ISSN :
0146-0404
eISSN :
1552-5783
Publisher :
Assoc Research Vision Ophthalmology Inc, Bethesda, United States - Maryland
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