April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
The Urokinase Receptor-Derived Peptide UPARANT Inhibits Pathological Retinal Angiogenesis
Author Affiliations & Notes
  • Dario Rusciano
    Scientific Department, Sooft Spa, Roma, Italy
  • Sara Rezzola
    Dept of Molecular and Translational Medicine, University, Brescia, Italy
  • Mirella Belleri
    Dept of Molecular and Translational Medicine, University, Brescia, Italy
  • Francesco Semeraro
    Ophthalmology, University, Brescia, Italy
  • Massimo Dal Monte
    Biology, University, Pisa, Italy
  • Paola Bagnoli
    Biology, University, Pisa, Italy
  • Lucia Morbidelli
    Life Sciences, University, Siena, Italy
  • Marina Ziche
    Life Sciences, University, Siena, Italy
  • Maria Vincenza Carriero
    Experimental Oncology, Istituto Nazionale Tumori, Napoli, Italy
  • Marco Presta
    Dept of Molecular and Translational Medicine, University, Brescia, Italy
  • Footnotes
    Commercial Relationships Dario Rusciano, Sooft spa/Bioos srl (E); Sara Rezzola, Sooft spa/Bioos srl (F); Mirella Belleri, Sooft spa/Bioos srl (F); Francesco Semeraro, Sooft spa/Bioos srl (F); Massimo Dal Monte, Sooft spa/Bioos srl (F); Paola Bagnoli, Sooft spa/Bioos srl (F); Lucia Morbidelli, Sooft spa/Bioos srl (F); Marina Ziche, Sooft spa/Bioos srl (F); Maria Vincenza Carriero, Farmafelix (P); Marco Presta, Sooft spa/Bioos srl (F)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 5403. doi:https://doi.org/
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      Dario Rusciano, Sara Rezzola, Mirella Belleri, Francesco Semeraro, Massimo Dal Monte, Paola Bagnoli, Lucia Morbidelli, Marina Ziche, Maria Vincenza Carriero, Marco Presta; The Urokinase Receptor-Derived Peptide UPARANT Inhibits Pathological Retinal Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5403. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Pathological angiogenesis of the retina is a key component of irreversible causes of blindness. Vascular endothelial growth factor (VEGF) is a major inducer of retinal neovascularization and VEGF blockers have evolved over time. However, limitations to anti-VEGF therapies may exist and novel anti-angiogenic approaches are eagerly required. During the neovascularization process the urokinase-type plasminogen activator (uPA)/uPA receptor (uPAR) system sustains the proteolytic degradation of the extracellular matrix by sprouting endothelial cells. Here we studied the anti-angiogenic activity of Ac-L-Arg-Aib-L-Arg-D-Cα(Me)Phe-NH2 (UPARANT), a modified peptide derived from uPAR and able to interfere with uPAR/integrin interaction.

Methods: The anti-angiogenic potential of UPARANT was assessed in various angiogenesis assays on endothelia of different species and tissue origin, including VEGF-stimulated endothelial cell sprouting from human umbilical venous endothelial cell (HUVEC) spheroids and murine aortic ring or retina fragments, VEGF-induced neovessel formation in the chick embryo chorioallantoic membrane (CAM) and rabbit cornea, and pathological vascularization in a murine model of oxygen-induced retinopathy (OIR).

Results: When administered at picomolar concentrations, UPARANT prevents the invasion of a 3D fibrin gel by spheroids of HUVECs stimulated by VEGF. This occurred in the absence of a significant effect of UPARANT on HUVEC proliferation. In keeping with these in vitro findings, UPARANT caused a dose-dependent inhibition of endothelial cell sprouting on murine aortic rings and retina fragments embedded in 3D fibrin gels in the presence of VEGF as a pro-angiogenic stimulus. Furthermore, UPARANT caused a significant inhibition of VEGF-induced angiogenesis in the chick embryo CAM assay with no effect on embryonic development and survival. UPARANT exerted a significant anti-angiogenic activity also in vivo by topic administration in a rabbit cornea assay and by intravitreal injection in a murine model of OIR.

Conclusions: Taken together, these data indicate that UPARANT may represent a promising therapeutic agent for angiogenesis-dependent diseases, including pathological angiogenesis of the retina. Experiments are in progress to assess the effect of UPARANT on the angiogenic activity exerted in vitro and ex vivo by the human vitreous fluid samples collected from diabetic retinopathy patients.

Keywords: 700 retinal neovascularization • 609 neovascularization • 688 retina  
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