Back to Search
Start Over
Dose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type I: implications for clinical trials.
- Source :
-
Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2003 Jun; Vol. 44 (6), pp. 2791-7. - Publication Year :
- 2003
-
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.<br />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.<br />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.<br />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.
- Subjects :
- Adenoviridae genetics
Animals
Choroidal Neovascularization metabolism
Choroidal Neovascularization pathology
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 genetics
Plasminogen Activator Inhibitor 1 metabolism
RNA, Messenger metabolism
Recombinant Proteins
Reverse Transcriptase Polymerase Chain Reaction
Serine Proteinase Inhibitors genetics
Serine Proteinase Inhibitors metabolism
Choroidal Neovascularization physiopathology
Plasminogen Activator Inhibitor 1 administration & dosage
Serine Proteinase Inhibitors administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 0146-0404
- Volume :
- 44
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Investigative ophthalmology & visual science
- Publication Type :
- Academic Journal
- Accession number :
- 12766088
- Full Text :
- https://doi.org/10.1167/iovs.02-1179