title: Therapeutic Potential of Anti-Angiogenic Multitarget N,O-Sulfated E. Coli K5 Polysaccharide in Diabetic Retinopathy.
abstract: Vascular endothelial growth factor (VEGF) blockers have been developed for the treatment of proliferative diabetic retinopathy (PDR), the leading cause of visual impairments in the working-age population in the Western world. However, limitations to anti-VEGF therapies may exist because of the local production of other proangiogenic factors that may cause resistance to anti-VEGF interventions. Thus, novel therapeutic approaches targeting additional pathways are required. Here, we identified a sulfated derivative of the Escherichia coli polysaccharide K5 [K5-N,OS(H)] as a multitarget molecule highly effective in inhibiting VEGF-driven angiogenic responses in different in vitro, ex vivo, and in vivo assays, including a murine model of oxygen-induced retinopathy. Furthermore, K5-N,OS(H) binds a variety of heparin-binding angiogenic factors upregulated in PDR vitreous humor besides VEGF, thus inhibiting their biological activity. Finally, K5-N,OS(H) hampers the angiogenic activity exerted in vitro and in vivo by human vitreous fluid samples collected from patients with PDR. Together, the data provide compelling experimental evidence that K5-N,OS(H) represents an antiangiogenic multitarget molecule with potential implications for the therapy of pathologic neovessel formation in the retina of patients with PDR.
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: Massimo
authors.initials: M
authors.lastname: Dal Monte
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 Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Bugatti
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Chiodelli
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 Biology, University of Pisa, Pisa, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cammalleri
authors.affiliation: Department of Ophthalmology, University of Brescia, Brescia, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Cancarini
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Morbidelli
authors.affiliation: Glycores 2000, Milan, Italy.
authors.forename: Pasqua
authors.initials: P
authors.lastname: Oreste
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy marco.presta@unibs.it paola.bagnoli@unipi.it francesco.semeraro@unibs.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Bagnoli
authors.affiliation: Department of Ophthalmology, University of Brescia, Brescia, Italy marco.presta@unibs.it paola.bagnoli@unipi.it francesco.semeraro@unibs.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Semeraro
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy marco.presta@unibs.it paola.bagnoli@unipi.it francesco.semeraro@unibs.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Presta
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D016667:Bacterial Capsules; D016466:CHO Cells; D002642:Chick Embryo; D003412:Cricetulus; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D006493:Heparin / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D015861:Retinal Neovascularization / Q000188:drug therapy; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D014822:Vitreous Body / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; C050673:capsular polysaccharide K5; D006493:Heparin; D040301:Vascular Endothelial Growth Factor Receptor-2