title: Antiangiogenic Effectiveness of the Urokinase Receptor-Derived Peptide UPARANT in a Model of Oxygen-Induced Retinopathy.
abstract: OBJECTIVE
  Pharmacologic control of neovascularization is a promising approach for the treatment of retinal angiogenesis. UPARANT, an inhibitor of the urokinase-type plasminogen activator receptor (uPAR), inhibits VEGF-driven angiogenesis in vitro and in vivo. This study investigates for the first time the effectiveness of UPARANT in counteracting pathologic neovascularization in the retina.
  
  
  METHODS
  Murine retinal fragments and a mouse model of oxygen-induced retinopathy (OIR) were used. In mice with OIR, UPARANT-treated retinas were analyzed for avascular area and neovascular tuft formation. Levels of transcription and proangiogenic factors were determined. UPARANT effects on the blood-retinal barrier (BRB), visual function, retinal cytoarchitecture, and inflammatory markers were also assessed. Human umbilical vein endothelial cells (HUVECs) and chick embryo chorioallantoic membrane (CAM) in which angiogenesis was induced by the vitreous fluid from patients with proliferative diabetic retinopathy (PDR) were also used.
  
  
  RESULTS
  UPARANT reduced VEGF-induced angiogenesis in retinal fragments. In mice with OIR, UPARANT decreased neovascular response, VEGF, and VEGF receptor-2 activity. Transcription factors regulating VEGF expression were also reduced. UPARANT restored BRB integrity, recovered visual loss, and reduced levels of inflammatory markers. Restored electroretinogram does not involve any rescue in the retinal cytoarchitecture. Finally, UPARANT blocked PDR vitreous fluid-induced angiogenesis in HUVEC and CAM assays.
  
  
  CONCLUSIONS
  The finding that UPARANT is effective against neovascularization may help to establish uPAR as a target in the treatment of proliferative retinopathies. The potential application of UPARANT in retinal diseases is further supported by UPARANT capacity to counteract the angiogenic activity of PDR vitreous fluid.
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Dal Monte
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Rezzola
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cammalleri
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Belleri
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Locri
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Morbidelli
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Corsini
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Paganini
authors.affiliation: Department of Ophthalmology, University of Brescia, Brescia, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Semeraro
authors.affiliation: Department of Ophthalmology, University of Brescia, Brescia, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Cancarini
authors.affiliation: Sooft Italia Spa, Montegiorgio, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Rusciano
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Presta
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Bagnoli
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D001813:Blood-Retinal Barrier / Q000378:metabolism; D015153:Blotting, Western; D002642:Chick Embryo; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000008:administration & dosage*; D010100:Oxygen / Q000633:toxicity; D012164:Retinal Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D009842:Oligopeptides; C000594116:acetyl-arginyl-aminoisobutyryl-arginyl-C(alpha)-methylphenylalaninamide; D010100:Oxygen