Experimental Ophthalmology Laboratory of Liege
Experimental Ophthalmology Laboratory of Liege
University of Liège,
Pathology Tower (BC-3), Sart-Tilman, B-4000 Liège, BELGIUM
Phone : +32-4-366.72.75
Fax : +32-4-366.29.36

Rôle des protéinases et de leurs inhibiteurs dans les formes associées à une néovascularisation anormale sous-rétinienne. Caractérisation par l’étude de modèles animaux transgéniques et développements thérapeutiques.

Résumé de la thèse de doctorat en Sciences Biomédicales de Vincent LAMBERT défendue le 8 juillet 2005 à l'Université de Liège, Belgique

Ce travail a été réalisé au sein du Laboratoire de Biologie des Tumeurs et du Développement (LBTD)Laboratoire de Biologie des Tumeurs et du Développement (LBTD) des Professeurs Jean-Michel Foidart et Agnes Noël


1. La dégénérescence maculaire liée à l’âge
2. Traitements expérimentaux
3. But du travail
4. Chapitre 1: Rôle des Protéases à Sérine dans la Néovascularisation Choroïdienne
5. Chapitre 2: Rôle des Métalloprotéinases (MMPs) dans la Néovascularisation Choroïdienne
6. Discussion générale
6. Bibliographie

6. Bibliographie

Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE, . (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331: 1480-1487

Arlt M, Kopitz C, Pennington C, Watson KL, Krell HW, Bode W, Gansbacher B, Khokha R, Edwards DR, Kruger A (2002) Increase in gelatinase-specificity of matrix metalloproteinase inhibitors correlates with antimetastatic efficacy in a T-cell lymphoma model. Cancer Res 62: 5543-5550

Bajou K, Maillard C, Jost M, Lijnen RH, Gils A, Declerck P, Carmeliet P, Foidart JM, Noel A (2004b) Host-derived plasminogen activator inhibitor-1 (PAI-1) concentration is critical for in vivo tumoral angiogenesis and growth. Oncogene 23: 6986-6990

Bajou K, Masson V, Gerard RD, Schmitt PM, Albert V, Praus M, Lund LR, Frandsen TL, Brunner N, Dano K, Fusenig NE, Weidle U, Carmeliet G, Loskutoff D, Collen D, Carmeliet P, Foidart JM, Noel A (2001) The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. J Cell Biol 152: 777-784

Balbin M, Fueyo A, Tester AM, Pendas AM, Pitiot AS, Astudillo A, Overall CM, Shapiro SD, Lopez-Otin C (2003) Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nat Genet 35: 252-257

Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2: 737-744

Berglin L, Sarman S, van dP, I, Steen B, Ming Y, Itohara S, Seregard S, Kvanta A (2003) Reduced choroidal neovascular membrane formation in matrix metalloproteinase-2-deficient mice. Invest Ophthalmol Vis Sci 44: 403-408

Blaauwgeers HG, Holtkamp GM, Rutten H, Witmer AN, Koolwijk P, Partanen TA, Alitalo K, Kroon ME, Kijlstra A, van Hinsbergh VW, Schlingemann RO (1999) Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris. Evidence for a trophic paracrine relation. Am J Pathol 155: 421-428

Blei F, Wilson EL, Mignatti P, Rifkin DB (1993) Mechanism of action of angiostatic steroids: suppression of plasminogen activator activity via stimulation of plasminogen activator inhibitor synthesis. J Cell Physiol 155: 568-578

Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 1477: 267-283

Calabrese EJ (2001) Estrogen and related compounds: biphasic dose responses. Crit Rev Toxicol 31: 503-515

Carmeliet P, Moons L, Dewerchin M, Rosenberg S, Herbert JM, Lupu F, Collen D (1998) Receptor-independent role of urokinase-type plasminogen activator in pericellular plasmin and matrix metalloproteinase proteolysis during vascular wound healing in mice. J Cell Biol 140: 233-245

Chang C, Werb Z (2001) The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis. Trends Cell Biol 11: S37-S43

Coussens LM, Tinkle CL, Hanahan D, Werb Z (2000) MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103: 481-490

Czekay RP, Aertgeerts K, Curriden SA, Loskutoff DJ (2003) Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J Cell Biol 160: 781-791

Czekay RP, Loskutoff DJ (2004) Unexpected role of plasminogen activator inhibitor 1 in cell adhesion and detachment. Exp Biol Med (Maywood ) 229: 1090-1096

D'Amico DJ, Goldberg MF, Hudson H, Jerdan JA, Krueger S, Luna S, Robertson SM, Russell S, Singerman L, Slakter JS, Sullivan EK, Yannuzzi L, Zilliox P (2003) Anecortave acetate as monotherapy for the treatment of subfoveal lesions in patients with exudative age-related macular degeneration (AMD): interim (month 6) analysis of clinical safety and efficacy. Retina 23: 14-23

Das A, McGuire PG, Eriqat C, Ober RR, DeJuan E Jr, Williams GA, McLamore A, Biswas J, Johnson DW (1999a) Human diabetic neovascular membranes contain high levels of urokinase and metalloproteinase enzymes. Invest Ophthalmol Vis Sci 40: 809-813

Das A, McLamore A, Song W, McGuire PG (1999b) Retinal neovascularization is suppressed with a matrix metalloproteinase inhibitor. Arch Ophthalmol 117: 498-503

DeFaller JM, Clark AF (2000) A new pharmacological treatment for angiogenesis. Taylor HR (ed) pp 159-181. Kugler Publication: The Hague

Degryse B, Neels JG, Czekay RP, Aertgeerts K, Kamikubo Y, Loskutoff DJ (2004) The low density lipoprotein receptor-related protein is a motogenic receptor for plasminogen activator inhibitor-1. J Biol Chem 279: 22595-22604

Devy L, Blacher S, Grignet-Debrus C, Bajou K, Masson V, Gerard RD, Gils A, Carmeliet G, Carmeliet P, Declerck PJ, Noel A, Foidart JM (2002) The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB J 16: 147-154

Dong Z, Kumar R, Yang X, Fidler IJ (1997) Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell 88: 801-810

Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2: 161-174

Engsig MT, Chen QJ, Vu TH, Pedersen AC, Therkidsen B, Lund LR, Henriksen K, Lenhard T, Foged NT, Werb Z, Delaisse JM (2000) Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones. J Cell Biol 151: 879-889

Ezekowitz RA, Mulliken JB, Folkman J (1992) Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med 326: 1456-1463

Gately S, Twardowski P, Stack MS, Cundiff DL, Grella D, Castellino FJ, Enghild J, Kwaan HC, Lee F, Kramer RA, Volpert O, Bouck N, Soff GA (1997) The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. Proc Natl Acad Sci U S A 94: 10868-10872

Grant MB, Ellis EA, Caballero S, Mames RN (1996) Plasminogen activator inhibitor-1 overexpression in nonproliferative diabetic retinopathy. Exp Eye Res 63: 233-244

Grossniklaus HE, Cingle KA, Yoon YD, Ketkar N, L'Hernault N, Brown S (2000) Correlation of histologic 2-dimensional reconstruction and confocal scanning laser microscopic imaging of choroidal neovascularization in eyes with age-related maculopathy. Arch Ophthalmol 118: 625-629

Hackett SF, Campochiaro PA (1993) Modulation of plasminogen activator inhibitor-1 and urokinase in retinal pigmented epithelial cells. Invest Ophthalmol Vis Sci 34: 2055-2061

Hattenbach LO, Allers A, Gumbel HO, Scharrer I, Koch FH (1999) Vitreous concentrations of TPA and plasminogen activator inhibitor are associated with VEGF in proliferative diabetic vitreoretinopathy. Retina 19: 383-389

Hiraoka N, Allen E, Apel IJ, Gyetko MR, Weiss SJ (1998) Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins. Cell 95: 365-377

Holmbeck K, Bianco P, Caterina J, Yamada S, Kromer M, Kuznetsov SA, Mankani M, Robey PG, Poole AR, Pidoux I, Ward JM, Birkedal-Hansen H (1999) MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99: 81-92

Itoh T, Matsuda H, Tanioka M, Kuwabara K, Itohara S, Suzuki R (2002) The role of matrix metalloproteinase-2 and matrix metalloproteinase-9 in antibody-induced arthritis. J Immunol 169: 2643-2647

Itoh T, Tanioka M, Yoshida H, Yoshioka T, Nishimoto H, Itohara S (1998) Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res 58: 1048-1051

Janzer RC, Raff MC (1987) Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325: 253-257

Jiang Y, Goldberg ID, Shi YE (2002) Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene 21: 2245-2252

Jin M, Kashiwagi K, Iizuka Y, Tanaka Y, Imai M, Tsukahara S (2001) Matrix metalloproteinases in human diabetic and nondiabetic vitreous. Retina 21: 28-33

Johnson MD, Kim HR, Chesler L, Tsao-Wu G, Bouck N, Polverini PJ (1994) Inhibition of angiogenesis by tissue inhibitor of metalloproteinase. J Cell Physiol 160: 194-202

Kadonosono K, Yazama F, Itoh N, Sawada H, Ohno S (1999) Expression of matrix metalloproteinase-7 in choroidal neovascular membranes in age-related macular degeneration. Am J Ophthalmol 128: 382-384

Kamei M, Hollyfield JG (1999) TIMP-3 in Bruch's membrane: changes during aging and in age-related macular degeneration. Invest Ophthalmol Vis Sci 40: 2367-2375

Kosano H, Okano T, Katsura Y, Noritake M, Kado S, Matsuoka T, Nishigori H (1999) ProMMP-9 (92 kDa gelatinase) in vitreous fluid of patients with proliferative diabetic retinopathy. Life Sci 64: 2307-2315

Kvanta A, Algvere PV, Berglin L, Seregard S (1996) Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci 37: 1929-1934

Kvanta A, Shen WY, Sarman S, Seregard S, Steen B, Rakoczy E (2000) Matrix metalloproteinase (MMP) expression in experimental choroidal neovascularization. Curr Eye Res 21: 684-690

Lambert V, Munaut C, Carmeliet P, Gerard RD, Declerck PJ, Gils A, Claes C, Foidart JM, Noel A, Rakic JM (2003a) Dose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type I: implications for clinical trials. Invest Ophthalmol Vis Sci 44: 2791-2797

Lambert V, Munaut C, Jost M, Noel A, Werb Z, Foidart JM, Rakic JM (2002) Matrix metalloproteinase-9 contributes to choroidal neovascularization. Am J Pathol 161: 1247-1253

Lambert V, Munaut C, Noel A, Frankenne F, Bajou K, Gerard R, Carmeliet P, Defresne MP, Foidart JM, Rakic JM (2001) Influence of plasminogen activator inhibitor type 1 on choroidal neovascularization. FASEB J 15: 1021-1027

Lambert V, Wielockx B, Munaut C, Galopin C, Jost M, Itoh T, Werb Z, Baker A, Libert C, Krell HW, Foidart JM, Noel A, Rakic JM (2003b) MMP-2 and MMP-9 synergize in promoting choroidal neovascularization. FASEB J 17: 2290-2292

Liu G, Shuman MA, Cohen RL (1995) Co-expression of urokinase, urokinase receptor and PAI-1 is necessary for optimum invasiveness of cultured lung cancer cells. Int J Cancer 60: 501-506

Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, Baxter BT (2002) Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 110: 625-632

Lopez PF, Grossniklaus HE, Lambert HM, Aaberg TM, Capone A, Jr., Sternberg P, Jr., L'Hernault N (1991) Pathologic features of surgically excised subretinal neovascular membranes in age-related macular degeneration. Am J Ophthalmol 112: 647-656

Lopez PF, Lambert HM, Grossniklaus HE, Sternberg P, Jr. (1993) Well-defined subfoveal choroidal neovascular membranes in age-related macular degeneration. Ophthalmology 100: 415-422

Majid MA, Smith VA, Easty DL, Baker AH, Newby AC (2002) Sorsby's fundus dystrophy mutant tissue inhibitors of metalloproteinase-3 induce apoptosis of retinal pigment epithelial and MCF-7 cells. FEBS Lett 529: 281-285

Majka S, McGuire P, Colombo S, Das A (2001) The balance between proteinases and inhibitors in a murine model of proliferative retinopathy. Invest Ophthalmol Vis Sci 42: 210-215

Manes S, Llorente M, Lacalle RA, Gomez-Mouton C, Kremer L, Mira E, Martinez A (1999) The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in DU-145 carcinoma cells. J Biol Chem 274: 6935-6945

Maquoi E, Sounni NE, Devy L, Olivier F, Frankenne F, Krell HW, Grams F, Foidart JM, Noel A (2004) Anti-invasive, antitumoral, and antiangiogenic efficacy of a pyrimidine-2,4,6-trione derivative, an orally active and selective matrix metalloproteinases inhibitor. Clin Cancer Res 10: 4038-4047

Masos T, Dan JA, Miskin R (2000) Plasminogen activator inhibitor-1 mRNA is localized in the ciliary epithelium of the rodent eye. Invest Ophthalmol Vis Sci 41: 1006-1011

McMahon GA, Petitclerc E, Stefansson S, Smith E, Wong MK, Westrick RJ, Ginsburg D, Brooks PC, Lawrence DA (2001) Plasminogen activator inhibitor-1 regulates tumor growth and angiogenesis. J Biol Chem 276: 33964-33968

Miller JW, Stinson WG, Folkman J (1993) Regression of experimental iris neovascularization with systemic alpha-interferon. Ophthalmology 100: 9-14

Montesano R, Pepper MS, Mohle-Steinlein U, Risau W, Wagner EF, Orci L (1990) Increased proteolytic activity is responsible for the aberrant morphogenetic behavior of endothelial cells expressing the middle T oncogene. Cell 62: 435-445

Noel A, Bajou K, Masson V, Devy L, Frankenne F, Rakic JM, Lambert V, Carmeliet P, Foidart JM (1999) Regulation of cancer invasion and vascularization by plasminogen activator inhibitor-1. Fibrinolysis Proteolysis 13: 220-225

Oh H, Takagi H, Takagi C, Suzuma K, Otani A, Ishida K, Matsumura M, Ogura Y, Honda Y (1999) The potential angiogenic role of macrophages in the formation of choroidal neovascular membranes. Invest Ophthalmol Vis Sci 40: 1891-1898

Okamoto N, Tobe T, Hackett SF, Ozaki H, Vinores MA, LaRochelle W, Zack DJ, Campochiaro PA (1997) Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. Am J Pathol 151: 281-291

Overall CM, Lopez-Otin C (2002) Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer 2: 657-672

Penn JS, Rajaratnam VS (2003) Inhibition of retinal neovascularization by intravitreal injection of human rPAI-1 in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 44: 5423-5429

Penn JS, Rajaratnam VS, Collier RJ, Clark AF (2001) The effect of an angiostatic steroid on neovascularization in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 42: 283-290

Pepper MS (2001) Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis. Arterioscler Thromb Vasc Biol 21: 1104-1117

Pepper MS, Montesano R (1990) Proteolytic balance and capillary morphogenesis. Cell Differ Dev 32: 319-327

Pepper MS, Sappino AP, Montesano R, Orci L, Vassalli JD (1992) Plasminogen activator inhibitor-1 is induced in migrating endothelial cells. J Cell Physiol 153: 129-139

Pharmacological Therapy for Macular Degeneration Study Group (1997) Interferon alfa-2a is ineffective for patients with choroidal neovascularization secondary to age-related macular degeneration. Results of a prospective randomized placebo-controlled clinical trial. Arch Ophthalmol 115: 865-872

Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE (1995) Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci U S A 92: 905-909

Qi JH, Ebrahem Q, Yeow K, Edwards DR, Fox PL, Anand-Apte B (2002) Expression of Sorsby's fundus dystrophy mutations in human retinal pigment epithelial cells reduces matrix metalloproteinase inhibition and may promote angiogenesis. J Biol Chem 277: 13394-13400

Rakic JM, Lambert V, Munaut C, Bajou K, Peyrollier K, Alvarez-Gonzalez ML, Carmeliet P, Foidart JM, Noel A (2003) Mice without uPA, tPA, or plasminogen genes are resistant to experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 44: 1732-1739

Ruiz A, Brett P, Bok D (1996) TIMP-3 is expressed in the human retinal pigment epithelium. Biochem Biophys Res Commun 226: 467-474

Salzmann J, Limb GA, Khaw PT, Gregor ZJ, Webster L, Chignell AH, Charteris DG (2000) Matrix metalloproteinases and their natural inhibitors in fibrovascular membranes of proliferative diabetic retinopathy. Br J Ophthalmol 84: 1091-1096

Simpson-Haidaris PJ, Rybarczyk B (2001) Tumors and fibrinogen. The role of fibrinogen as an extracellular matrix protein. Ann N Y Acad Sci 936: 406-425

Smalley DM, Fitzgerald JE, Taylor DM, Cone RE, O'Rourke J (1994) Tissue plasminogen activator activity in human aqueous humor. Invest Ophthalmol Vis Sci 35: 48-53

Soff GA, Sanderowitz J, Gately S, Verrusio E, Weiss I, Brem S, Kwaan HC (1995) Expression of plasminogen activator inhibitor type 1 by human prostate carcinoma cells inhibits primary tumor growth, tumor-associated angiogenesis, and metastasis to lung and liver in an athymic mouse model. J Clin Invest 96: 2593-2600

Soubrane, G., De Smet, M. D., and Schmidt-Erfurth, U. Anecortave acetate for the treatment of AMD patients with subfoveal choroidal neovascularisation (CNV). Ophthalmic Res. 34, 3312. 2002. Ref Type: Abstract

Spraul CW, Lang GE, Grossniklaus HE, Lang GK (1999) 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 44 Suppl 1: S10-S32

Steen B, Sejersen S, Berglin L, Seregard S, Kvanta A (1998) Matrix metalloproteinases and metalloproteinase inhibitors in choroidal neovascular membranes. Invest Ophthalmol Vis Sci 39: 2194-2200

Stefansson S, Lawrence DA (2003) Old dogs and new tricks: proteases, inhibitors, and cell migration. Sci STKE 2003: e24

Stefansson S, McMahon GA, Petitclerc E, Lawrence DA (2003) Plasminogen activator inhibitor-1 in tumor growth, angiogenesis and vascular remodeling. Curr Pharm Des 9: 1545-1564

Stefansson S, Petitclerc E, Wong MK, McMahon GA, Brooks PC, Lawrence DA (2001) Inhibition of angiogenesis in vivo by plasminogen activator inhibitor-1. J Biol Chem 276: 8135-8141

Steinkamp GW, Hattenbach LO, Heider HW, Scharrer I (1993) [Plasminogen activator and PAI. Detection in aqueous humor of the human eye]. Ophthalmologe 90: 73-75

Takahashi T, Nakamura T, Hayashi A, Kamei M, Nakabayashi M, Okada AA, Tomita N, Kaneda Y, Tano Y (2000) Inhibition of experimental choroidal neovascularization by overexpression of tissue inhibitor of metalloproteinases-3 in retinal pigment epithelium cells. Am J Ophthalmol 130: 774-781

Tobe T, Ortega S, Luna JD, Ozaki H, Okamoto N, Derevjanik NL, Vinores SA, Basilico C, Campochiaro PA (1998) Targeted disruption of the FGF2 gene does not prevent choroidal neovascularization in a murine model. Am J Pathol 153: 1641-1646

Wang Y, Gillies C, Cone RE, O'Rourke J (1995) Extravascular secretion of t-PA by the intact superfused choroid. Invest Ophthalmol Vis Sci 36: 1625-1632

Weber BH, Vogt G, Pruett RC, Stohr H, Felbor U (1994) Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy. Nat Genet 8: 352-356

Yamada E, Tobe T, Yamada H, Okamoto N, Zack DJ, Werb Z, Soloway PD, Campochiaro PA (2001) TIMP-1 promotes VEGF-induced neovascularization in the retina. Histol Histopathol 16: 87-97

Zhou A, Huntington JA, Pannu NS, Carrell RW, Read RJ (2003) How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration. Nat Struct Biol 10: 541-544

retour haut de la page accueil

Université de LiègeUniversité de Liège
Experimental Ophthalmology Laboratoryhttp://www.ophtalmo.ulg.ac.be
Laboratoire de biologie des tumeurs et du developpement http://www.lbtd.ulg.ac.be/
March 2009 - This page is made by Vincent LAMBERT under the responsability of Jean-Marie RAKIC