[en] PURPOSE. To evaluate the presence and potential involvement of members of the plasminogen/plasminogen activator (Plg/PA) system in the exudative form of age-related macular degeneration (AMD). METHODS. The expression of PA members mRNA was evaluated in human and experimental choroidal neovascularization (CNV) by RT-PCR. The presence and activity of PA was studied by immunofluorescence and in situ zymography. The influence of endogenous plasminogen (Plg), urokinase (uPA), tissue type plasminogen activator (tPA), and uPA receptor (uPAR) was explored in single-gene-deficient mice in a model of laser-induced CNV. RESULTS. Members of the Plg/PA system were present both in human and murine CNV. The absence of Pig, uPA, or tPA significantly decreased the development of experimental CNV compared with wild-type or uPAR-deficient mice. This effect could be attributable, partly to a modulation of matrix metalloproteinase activity, but also to an accumulation of fibrinogen-fibrin in the laser-induced wounds. CONCLUSIONS. Together with previous work done by the authors, this study indicates that choroidal neovascularization is extremely sensitive to the modulation of Plg/PA system activity. This may provide a new strategy for the treatment of exudative AMD.
Disciplines :
Ophthalmology
Author, co-author :
Rakic, Jean-Marie ; Université de Liège - ULiège > Département des sciences cliniques > Ophtalmologie
Lambert, Vincent ; Centre Hospitalier Universitaire de Liège - CHU > Ophtalmologie
Munaut, Carine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Bajou, Khalid ; Université de Liège - ULiège > Département des sciences de la vie > Biologie et génétique moléculaire
Peyrollier, Karine
Alvarez Gonzalez, Maria-Luz ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Carmeliet, Peter
Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Language :
English
Title :
Mice without uPA, tPA, or plasminogen genes are resistant to experimental choroidal neovascularization
Publication date :
April 2003
Journal title :
Investigative Ophthalmology and Visual Science
ISSN :
0146-0404
eISSN :
1552-5783
Publisher :
Assoc Research Vision Ophthalmology Inc, Bethesda, United States - Maryland
Campochiaro PA. Retinal and choroidal neovascularization. J Cell Physiol. 2000;184:301-310.
Pepper MS. Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis. Arterioscler Thromb Vasc Biol. 2001;21:1104-1117.
Blasi F. Proteolysis, cell adhesion, chemotaxis, and invasiveness are regulated by the u-PA-u-PAR-PAI-1 system. Thromb Haemost. 1999;82:298-304.
Stetler-Stevenson WG. Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest. 1999; 103:1237-1241.
Bergers G, Brekken R, McMahon G, et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol. 2000;2:737-744.
Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;3:161-174.
Andreasen PA, Kjoller L, Christensen L, Duffy MJ. The urokinasetype plasminogen activator system in cancer metastasis: a review. Int J Cancer. 1997;72:1-22.
Cavallaro U, Tenan M, Castelli V, et al. Response of bovine endothelial cells to FGF-2 and VEGF is dependent on their site of origin: relevance to the regulation of angiogenesis. J Cell Biochem. 2001; 82:619-633.
Carmeliet P, Collen D. Genetic analysis of blood vessel formation: role of endothelial versus smooth muscle cells. Trend Cardiovasc Med. 1997;7:271-281.
Devy L, Blacher S, Grignet-Debrus C, et al. The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB J 2002;16:147-154.
Bajou K, Noel A, Gerard RD, et al. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med. 1998;4:923-928.
Bajou K, Masson V, Gerard RD, et al. The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin: implications for antiangiogenic strategies. J Cell Biol. 2001;152:777-784.
Berman M, Winthrop S, Ausprunk D, Rose J, Langer R, Gage J. Plasminogen activator (urokinase) causes vascularization of the cornea. Invest Ophthalmol Vis Sci. 1982;22:191-199.
Grant MB, Guay C. Plasminogen activator production by human retinal endothelial cells of nondiabetic and diabetic origin. Invest Ophthalmol Vis Sci. 1991;32:53-64.
Das A, McGuire PG, Eriqat C, et al. Human diabetic neovascular membranes contain high levels of urokinase and metalloproteinase enzymes. Invest Ophthalmol Vis Sci. 1999;40:809-813.
Hattenbach LO, Allers A, Gumbel HO, Scharrer I, Koch FH. Vitreous concentrations of TPA and plasminogen activator inhibitor are associated with VEGF in proliferative diabetic vitreoretinopathy. Retina. 1999;19:383-389.
Lambert V, Munaut C, Noel A, et al. Influence of plasminogen activator inhibitor type I on choroidal neovascularization. FASEB J. 2001;15:1021-1027.
Lopez PF, Grossniklaus HE, Lambert HM, et al. Pathologic features of surgically excised subretinal neovascular membranes in agerelated macular degeneration. Am J Ophthalmol. 1991;112:647-656.
Lopez PF, Lambert HM, Grossniklaus HE, Sternberg P Jr. Welldefined subfoveal choroidal neovascular membranes in age-related macular degeneration. Ophthalmology. 1993;100:415-422.
Lambert V, Munaut C, Noel A, Werb Z, Foidart J-M, Rakic J-M. MMP-9 contributes to choroidal neovascularization. Am J Pathol. 2002;161:1247-1253.
Carmeliet P, Schoonjans L, Kieckens L, et al. Physiological consequences of loss of plasminogen activator gene function in mice. Nature. 1994;368:419-424.
Carmeliet P, Collen D. Development and disease in proteinasedeficient mice: role of the plasminogen, matrix metalloproteinase and coagulation system. Thromb Res. 1998;91:255-285.
Ploplis VA, French EL, Carmeliet P, Collen D, Plow EF. Plasminogen deficiency differentially affects recruitment of inflammatory cell populations in mice. Blood. 1998;91:2005-2009.
Munaut C, Noel A, Weidle UH, Krell HW, Foidart JM. Modulation of the expression of interstitial and type-IV collagenases in coculture of HT1080 fibrosarcoma cells and fibroblasts. Invasive Metastasis. 1995;15:169-178.
Bugge TH, Kombrinck KW, Flick MJ, Daugherty CC, Danton MJ, Degen JL. Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency. Cell. 1996;87:709-719.
Wang Y, Gillies C, Cone RE, O'Rourke J. Extravascular secretion of t-PA by the intact superfused choroid. Invest Ophthalmol Vis Sci. 1995;36:1625-1632.
Hackett SF, Campochiaro PA. Modulation of plasminogen activator inhibitor-1 and urokinase in retinal pigmented epithelial cells. Invest Ophthalmol Vis Sci. 1993;34:2055-2061.
Das A, McLamore A, Song W, McGuire PG. Retinal neovascularization is suppressed with a matrix metalloproteinase inhibitor. Arch Ophthalmol. 1999;117:498-503.
Carmeliet P, Moons L, Dewerchin M, et al. Receptor-independent role of urokinase-type plasminogen activator in pericellular plasmin and matrix metalloproteinase proteolysis during vascular wound healing in mice. J Cell Biol. 1998;140:233-245.
Grossniklaus HE, Cingle KA, Yoon YD, Ketkar N, L'Hernault N, Brown S. Correlation of histologic 2-dimensional reconstruction and confocal scanning laser microscopic imaging of choroidal neovascularization in eyes with age-related maculopathy. Arch Ophthalmol. 2000;118:625-629.
Spraul CW, Lang GE, Grossniklaus HE, Lang GK. Histologic and morphometric analysis of the choroid, Bruch's membrane, and retinal pigment epithelium in postmortem eyes with age-related macular degeneration and histologic examination of surgically excised choroidal neovascular membranes. Surv Ophthalmol. 1999;44:10-32.
Hiraoka N, Allen E, Apel IJ, Gyetko MR, Weiss SJ. Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins. Cell. 1998;95:365-377.
Diaz VM, Planaguma J, Thomson TM, Reventos J, Paciucci R. Tissue plasminogen activator is required for the growth, invasion, and angiogenesis of pancreatic tumor cells. Gastroenterology. 2002;122:806-819.
Heymans S, Luttun A, Nuyens D, et al. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat Med. 1999;5:1135-1142.
Rifkin DB, Mazzieri R, Munger JS, Noguera I, Sung J. Proteolytic control of growth factor availability. APMIS. 1999;107:80-85.