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.

Heparin impairs angiogenic signaling and compensatory lung growth after left pneumonectomy

“…Analagous to its role in FGF signaling, exogenous heparin, especially at a lower molecular weight, inhibits VEGF’s angiogenic effects on endothelial cells[10]. Multiple studies have discovered other heparin-like compounds that can exert similar inhibitory effects on angiogenesis in efforts to develop new anti-tumor therapies[11–15]. …”

Vascular Endothelial Growth Factor in the Vitreous of Proliferative Diabetic Retinopathy Patients: Chasing a Hiding Prey?

“…The limited accessibility of vitreal VEGF was confirmed when different VEGFblocking drugs were evaluated for their capacity to inhibit the sprouting of human endothelial cell spheroids triggered by rVEGF or by a 1:4 dilution of the PDR vitreous (5). To this end, we used two pools of PDR vitreous from five and three patients with type 2 diabetes, respectively (six males, two females; mean 6 SD age: 61 6 17 years, diabetes duration: 16 6 6 years).…”

“…In the endothelial sprouting assay, rVEGF is active at concentrations $5.0 ng/mL (5). In contrast, rVEGF induced a significant biological response only at doses $500 ng/mL when tested in the presence of a 1:4 dilution of vitreous samples containing levels of vitreal VEGF below the limits of detection by ELISA and WB.…”

Inflammation and N-formyl peptide receptors mediate the angiogenic activity of human vitreous humour in proliferative diabetic retinopathy

“…Even though antiangiogenic vascular endothelial growth factor (VEGF) inhibitors are widely used in PDR therapy [2], several limitations to anti-VEGF interventions exist [6]. Furthermore, production of other angiogenic factors and proinflammatory mediators may nullify and/or cause resistance to anti-VEGF therapies [6,7]. Angiogenesis and inflammation are closely related processes that play a pivotal role in ocular diseases associated with retinal neovascularisation [5,8,9].…”

“…The study of the biological effects exerted by PDR vitreous fluid ('PDR vitreous') on endothelial cells may represent a useful tool to investigate the relationship between neovascular and inflammatory responses in preclinical experimental models. PDR vitreous contains high levels of pro-angiogenic and proinflammatory mediators [19,20] and stimulates angiogenesis in vitro and in vivo, whereas no angiogenic response is elicited by vitreous fluid from patients with a macular hole [7,17,[21][22][23]. However, no data are available about the capacity of PDR vitreous to exert proinflammatory responses in endothelium, their relationship with its ability to stimulate neovessel formation or the role of FPRs in this process.…”