Inhibition of Choroidal Neovascularization by a Peptide Inhibitor ofthe Urokinase Plasminogen Activator and Receptor System in a Mouse Model | Ophthalmology | JAMA Ophthalmology | JAMA Network
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Tobe  TOrtega  SLuna  JD  et al.  Targeted disruption of the FGF2 gene does not prevent choroidal neovascularizationin a murine model.  Am J Pathol 1998;1531641- 1646PubMedGoogle ScholarCrossref
Pepper  MS Extracellular proteolysis and angiogenesis.  Thromb Haemost 2001;86346- 355PubMedGoogle Scholar
Pepper  MS Role of the matrix metalloproteinase and plasminogen activator-plasminsystems in angiogenesis.  Arterioscler Thromb Vasc Biol 2001;211104- 1117PubMedGoogle ScholarCrossref
Rabbani  SAMazar  AP The role of plasminogen activator system in angiogenesis and metastasis.  Surg Oncol Clin N Am 2001;10393- 415PubMedGoogle Scholar
Czekay  RPAertgeerts  KCurriden  SALoskutoff  DJ Plasminogen activator inhibitor-1 detaches cells from extracellularmatrices by inactivating integrins.  J Cell Biol 2003;160781- 791PubMedGoogle ScholarCrossref
Das  AMcLamore  ASong  WMcGuire  PG Retinal neovascularization is suppressed with a MMP inhibitor.  Arch Ophthalmol 1999;117498- 503PubMedGoogle ScholarCrossref
Das  AMcGuire  PGEriqat  C  et al.  Human neovascular membranes contain high levels of urokinase and metalloproteinaseenzymes.  Invest Ophthalmol Vis Sci 1999;40809- 813PubMedGoogle Scholar
McGuire  PGJones  TWTalarico  NWarren  EDas  A The urokinase/urokinase receptor system in retinal neovascularization:inhibition by Å6 suggests a new therapeutic target.  Invest Ophthalmol Vis Sci 2003;442736- 2742PubMedGoogle ScholarCrossref
Guo  YHigazi  AAArakelian  A  et al.  A peptide derived from the nonreceptor binding region of urokinaseplasminogen activator (uPA) inhibits tumor progression and angiogenesis andinduces tumor cell death in vivo.  FASEB J 2000;141400- 1410PubMedGoogle ScholarCrossref
Mishima  KMazar  AGown  A  et al.  A peptide derived from the nonreceptor region of urokinase plasminogenactivator inhibits glioblastoma growth and angiogenesis in vivo in combinationwith cisplatin.  Proc Natl Acad Sci U S A 2000;978484- 8489PubMedGoogle ScholarCrossref
Rakic  JMLambert  VMunaut  C  et al.  Mice without uPA, tPA, or plasminogen genes are resistant to experimentalchoroidal neovascularization.  Invest Ophthalmol Vis Sci 2003;441732- 1739PubMedGoogle ScholarCrossref
Edelman  JLCastro  MR Quantitative image analysis of laser-induced choroidal neovascularizationin rat.  Exp Eye Res 2000;71523- 533PubMedGoogle ScholarCrossref
Mignatti  PRifkin  D Biology and biochemistry of proteinases in tumor invasion.  Physiol Rev 1993;73161- 195PubMedGoogle Scholar
Andreasen  PAEgelund  RPetersen  HH The plasminogen activation system in tumor growth, invasion, and metastasis.  Cell Mol Life Sci 2000;5725- 40PubMedGoogle ScholarCrossref
Blasi  FVasalli  JDDano  K Urokinase type plasminogen activator proenzyme, receptors and inhibitors.  J Cell Biol 1987;104801- 804PubMedGoogle ScholarCrossref
Blasi  FCarmeliet  P uPAR: a versatile signaling orchestrator.  Nat Rev Mol Cell Biol 2002;3932- 943PubMedGoogle ScholarCrossref
Kroon  MEKoolwijk  Pvan der Vecht  Bvan Hinsbergh  VWM Urokinase receptor expression on human microvascular endothelial cellsis increased by hypoxia: implications for capillary-tube formation in a fibrinmatrix.  Blood 2000;962775- 2783PubMedGoogle Scholar
Ishida  SUsui  TYamashiro  K  et al.  VEGF(164) mediated inflammation is required for pathological, but notphysiological, ischemia-induced retinal neovascularization.  J Exp Med 2003;198483- 489PubMedGoogle ScholarCrossref
Ishida  SYamashiro  KUsui  T  et al.  Leukocytes mediate retinal vascular remodeling during development andvaso-obliteration in disease.  Nat Med 2003;9781- 788Google ScholarCrossref
Campochiaro  PA Retinal and choroidal neovascularization.  J Cell Physiol 2000;184301- 310PubMedGoogle ScholarCrossref
Guo  YMazar  APLebrum  JJRabbani  SA An antiangiogenic urokinase-derived peptide combined with tamoxifendecreases tumor growth and metastasis in a syngeneic model of breast cancer.  Cancer Res 2002;624678- 4684PubMedGoogle Scholar
Treatment of Age-related Macular Degeneration with Photodynamic Therapy(TAP) Study Group, Photodynamic therapy of subfoveal choroidal neovascularization in age-relatedmacular degeneration with verteporfin: one-year results of 2 randomized clinicaltrials–TAP report.  Arch Ophthalmol 1999;1171329- 1345[erratum appears in Arch Ophthalmol. 2000;118:488].PubMedGoogle ScholarCrossref
Kramer  MMiller  JWMichaud  N  et al.  Liposomal benzoporphyrin derivative verteporfin photodynamic therapy:selective treatment of choroidal neovascularization in monkeys.  Ophthalmology 1996;103427- 438PubMedGoogle ScholarCrossref
Aiello  LPPierce  EAFoley  ED  et al.  Suppression of retinal neovascularization in vivo by inhibition ofvascular endothelial growth factor using soluble VEGF receptor chimeric proteins.  Proc Natl Acad Sci U S A 1995;9210457- 10461PubMedGoogle ScholarCrossref
Adamis  APShima  DTTolentino  MJ  et al.  Inhibition of vascular endothelial growth factor prevents ischemia-associatediris neovascularization in a non-human primate.  Arch Ophthalmol 1996;11466- 71PubMedGoogle ScholarCrossref
Ozaki  HSeo  MSOzaki  K  et al.  Blockade of vascular endothelial cell growth factor receptor signalingis sufficient to completely prevent retinal neovascularization.  Am J Pathol 2000;156697- 707PubMedGoogle ScholarCrossref
Saishin  YSaishin  YTakahashi  K  et al.  VEGF-TRAP(R1R2) suppresses choroidal neovascularization and VEGF-inducedbreakdown of the blood-retinal barrier.  J Cell Physiol 2003;195241- 248PubMedGoogle ScholarCrossref
Smith  LEKopchick  JJChen  W  et al.  Essential role of growth hormone in ischemia-induced retinal neovascularization.  Science 1997;2761706- 1709PubMedGoogle ScholarCrossref
Friedlander  MThesfeld  CLSugitta  M  et al.  Involvement of integrins avb3 and avb5 in ocular neovascular diseases.  Proc Natl Acad Sci U S A 1996;939764- 9769PubMedGoogle ScholarCrossref
Chavakis  ERiecke  BLin  J  et al.  Kinetics of integrin expression in the mouse model of proliferativeretinopathy and success of secondary intervention with cyclic RGD peptides.  Diabetologia 2002;45262- 267PubMedGoogle ScholarCrossref
Laboratory Sciences
December 2004

Inhibition of Choroidal Neovascularization by a Peptide Inhibitor ofthe Urokinase Plasminogen Activator and Receptor System in a Mouse Model

Author Affiliations

Author Affiliations: Departments of Surgery(Drs Das and McGuire) and Cell Biology and Physiology (Drs Das and McGuireand Messrs Boyd and Talarico), University of New Mexico School of Medicine,and New Mexico VA Health Care System (Dr Das), Albuquerque; and ÅngstromPharmaceuticals, San Diego, Calif (Dr Jones).

Arch Ophthalmol. 2004;122(12):1844-1849. doi:10.1001/archopht.122.12.1844

Objectives  To determine the role played by the urokinase plasminogen activator(uPA) and urokinase plasminogen activator receptor (uPAR) system in choroidalneovascularization (CNV) and whether inhibition of this system can suppressthe extent of CNV in an animal model.

Methods  Choroidal neovascularization was induced in mice by laser photocoagulationusing the slitlamp delivery system. Reverse transcriptase–polymerasechain reaction and immunocytochemical analysis were performed on the retinachoroids of these animals to examine the expression of uPAR. For 2 weeks followinglaser treatment, animals were injected intraperitoneally with a novel peptideinhibitor of the uPA-uPAR system (100 mg/kg twice a day every day, every otherday, and once a week). Control laser-treated animals receive an intraperitonealinjection of phosphate-buffered saline every day. Following treatment, animalswere perfused with fluorescein-labeled dextran, eyes were removed, and theareas of new vessels were examined in the retina-choroid whole mounts by fluorescencemicroscopy and quantitated using image analysis software.

Results  In this study, uPAR was found to be up-regulated in the choroidal tissuesof mice with laser-induced CNV. The uPAR was localized to the endothelialcells of the fibrovascular tissue within the CNV complex. Systemic administrationof the peptide inhibitor of the uPA-uPAR system resulted in a significantreduction of CNV (up to 94%). The response was found to be frequency-of-dosedependent. No toxic effects or tissue destruction was noted following thepeptide treatment.

Conclusions  Our results strongly suggest that up-regulation of the uPA-uPAR systemis an important step during CNV, and significant inhibition of CNV was seenwhen cell surface–associated uPA-uPAR activity was prevented with thepeptide inhibitor.

Clinical Relevance  Inhibition of the protease system (uPA-uPAR) may prove to be a potentialnovel antiangiogenic therapy for CNV as seen in age-related macular degeneration.