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Dose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type I: implications for
Vincent Lambert1, Carine Munaut, Peter Carmeliet
1Laboratory of Tumor and Development Biology, University of Liège, 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.
Insights
Plasminogen activator inhibitor type 1 (PAI-1) has dual pro- and antiangiogenic effects in choroidal neovascularization, depending on dosage. Its role in pathologic angiogenesis is primarily through antiproteolytic activity, not vitronectin binding.
Area of Science:
- Ophthalmology
- Molecular Biology
- Biochemistry
Background:
- Conflicting reports exist regarding plasminogen activator inhibitor type 1 (PAI-1) influence on pathologic angiogenesis.
- Age-related macular degeneration (AMD) involves exudative forms of choroidal neovascularization (CNV).
Purpose of the Study:
- To clarify the role of PAI-1 in pathologic angiogenesis, specifically in the context of exudative AMD.
- To reconcile contradictory findings on PAI-1's angiogenic effects.
Main Methods:
- Analyzed PAI-1 mRNA expression in human and murine CNV using RT-PCR.
- Investigated PAI-1's effects in a laser-induced CNV model in PAI-1 knockout and wild-type mice via recombinant PAI-1 injections.
- Explored PAI-1's mechanisms (proteolytic activity vs. vitronectin binding) using mutant proteins and gene vectors.
Main Results:
- PAI-1 expression was detected in human CNV and induced in experimental subretinal neovascularization.
- Recombinant PAI-1 exhibited dose-dependent pro- and antiangiogenic effects in mice.
- PAI-1 promotes choroidal angiogenesis primarily via its antiproteolytic activity, independent of vitronectin binding.
Conclusions:
- PAI-1's dual role in angiogenesis helps explain conflicting study results.
- Uncontrolled use of PAI-1-modulating drugs in clinical trials warrants caution.