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Dose-Dependent Modulation of Choroidal Neovascularization by Plasminogen Activator Inhibitor Type I: Implications for Clinical Trials

¹From the Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium; the ²Center for Transgene Technology and Gene Therapy, and ⁴Pharmaceutical Biology and Phytopharmacology, Katholieke Universiteit Leuven, Leuven, Belgium; the ³Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas; the ⁵Department of Ophthalmology, Middelheim Hospital, Antwerp, Belgium; and the ⁶Department of Ophthalmology, University Hospital, Liège, Belgium.

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.

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