Dose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type I: implications for clinical trials.
OBJECTIVE
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.
Lambert
Vincent
V
Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium.
Munaut
Carine
C
Carmeliet
Peter
P
Gerard
Robert D
RD
Declerck
Paul J
PJ
Gils
Ann
A
Claes
Carel
C
Foidart
Jean-Michel
JM
Noël
Agnès
A
Rakic
Jean-Marie
JM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D020256:Choroidal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007124:Immunoenzyme Techniques; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017395:Plasminogen Activator Inhibitor 1 / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors