title: Dose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type I: implications for clinical trials.
abstract: 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.
authors.affiliation: Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lambert
authors.forename: Carine
authors.initials: C
authors.lastname: Munaut
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Declerck
authors.forename: Ann
authors.initials: A
authors.lastname: Gils
authors.forename: Carel
authors.initials: C
authors.lastname: Claes
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.forename: Agnès
authors.initials: A
authors.lastname: Noël
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Rakic
mesh_terms: 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
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors