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

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.

• Authors: Vincent Lambert, Carine Munaut, Peter Carmeliet, Robert D Gerard, Paul J Declerck, Ann Gils, Carel Claes, Jean-Michel Foidart, Agnès Noël, Jean-Marie Rakic
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 44 Issue 6 Pg. 2791-7 (Jun 2003) ISSN: 0146-0404 [Print] United States
• PMID: 12766088 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Plasminogen Activator Inhibitor 1
• RNA, Messenger
• Recombinant Proteins
• Serine Proteinase Inhibitors

Topics

• Adenoviridae (genetics)
• Animals
• Choroidal Neovascularization (metabolism, pathology, physiopathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Fluorescent Antibody Technique, Indirect
• Gene Transfer Techniques
• Genetic Vectors
• Humans
• Immunoenzyme Techniques
• Injections, Intraperitoneal
• Male
• Mice
• Mice, Inbred C57BL
• Plasminogen Activator Inhibitor 1 (administration & dosage, genetics, metabolism)
• RNA, Messenger (metabolism)
• Recombinant Proteins
• Reverse Transcriptase Polymerase Chain Reaction
• Serine Proteinase Inhibitors (administration & dosage, genetics, metabolism)