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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.
AuthorsSara Rezzola, Massimo Dal Monte, Mirella Belleri, Antonella Bugatti, Paola Chiodelli, Michela Corsini, Maurizio Cammalleri, Anna Cancarini, Lucia Morbidelli, Pasqua Oreste, Paola Bagnoli, Francesco Semeraro, Marco Presta
JournalDiabetes (Diabetes) Vol. 64 Issue 7 Pg. 2581-92 (Jul 2015) ISSN: 1939-327X [Electronic] United States
PMID25695948 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
Chemical References
  • Angiogenesis Inhibitors
  • Vascular Endothelial Growth Factor A
  • capsular polysaccharide K5
  • Heparin
  • Vascular Endothelial Growth Factor Receptor-2
Topics
  • Angiogenesis Inhibitors (therapeutic use)
  • Animals
  • Bacterial Capsules
  • CHO Cells
  • Chick Embryo
  • Cricetulus
  • Diabetic Retinopathy (drug therapy)
  • Heparin (metabolism)
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Retinal Neovascularization (drug therapy)
  • Vascular Endothelial Growth Factor A (antagonists & inhibitors)
  • Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors)
  • Vitreous Body (drug effects)

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