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.
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: Maud Jost; Catherine Maillard; Julie Lecomte; Vincent Lambert; Marc Tjwa; Pierre Blaise; Maria-Luz Alvarez Gonzalez; Khalid Bajou; Silvia Blacher; Patrick Motte; Chantal Humblet; Marie Paule Defresne; Marc Thiry; Francis Frankenne; André Gothot; Peter Carmeliet; Jean-Marie Rakic; Jean-Michel Foidart; Agnès Noël Journal: Am J Pathol Date: 2007-08-23 Impact factor: 4.307
Authors: Esther J Kuiper; Peggy Roestenberg; Christoph Ehlken; Vincent Lambert; Henny Bloys van Treslong-de Groot; Karen M Lyons; Hans-Jürgen T Agostini; Jean-Marie Rakic; Ingeborg Klaassen; Cornelis J F Van Noorden; Roel Goldschmeding; Reinier O Schlingemann Journal: J Histochem Cytochem Date: 2007-07-11 Impact factor: 2.479