The Urokinase Receptor-Derived Peptide UPARANT Mitigates Angiogenesis in a Mouse Model of Laser-Induced Choroidal Neovascularization

Abstract

UPARANT mitigates laser-induced CNV by inhibiting angiogenesis and inflammation through an action on transcription factors encoding angiogenesis and inflammatory genes. The finding that UPARANT is effective against CNV may help to establish uPAR and its membrane partners as putative targets in the treatment of AMD.

A novel in vivo model of puncture-induced iris neovascularization

“…For VEGF-blockage, 6 mice were intravitreally injected with 1 μL of the recombinant VEGF receptor (VEGFR)1 Fc chimera protein (Bio-Techne Ltd., Abingdon, UK) at 1 gL -1 as previously described [12], while the fellow-eye was injected with phosphate-buffered saline (PBS; ThermoFisher Scientific Corp) as vehicle. For hypoxia-induced angiogenesis (see RPE medium conditioning), 12 mice were separated into 2 groups.…”

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

“…On this basis, allosteric inhibitors related to the uPAR 88-92 sequence and able to block the cross talk involving uPAR, FPRs and integrins were developed [16,40,41]. Among them, UPARANT competes with fMLF peptide for the binding to FPRs and is endowed with a significant anti-angiogenic activity in vitro and in vivo [16][17][18]. In addition, UPARANT suppresses the angiogenic activity of pooled PDR vitreous samples, pointing to this compound as a promising therapeutic for the treatment of inflammatory diseases associated with ocular angiogenesis, including PDR [17,18].…”

“…Various danger-associated molecular pattern host-derived peptides can activate FPRs [12]. Notably, the FPR ligands serum amyloid A, LL-37 and Hp (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) have been involved in the regulation of neovascularisation under inflammatory conditions [12]. High levels of serum amyloid A are detectable in the vitreous and plasma of PDR patients [43] and in eyes with macular oedema [44,45] whereas, to the best of our knowledge, no data are available about the levels of other FPR ligands in PDR vitreous.…”

“…Accordingly, the uPARderived tetrapeptide Ac-L-Arg-Aib-L-Arg-L-Cα(Me)Phe-NH 2 (UPARANT) competes with formyl-methionyl-leucyl phenylalanine (fMLF) peptide for binding to FPRs and is endowed with a significant anti-angiogenic activity in vitro and in vivo [16,17]. In addition, UPARANT prevents ocular angiogenesis and reduces the levels of inflammatory mediators in murine models of oxygen-induced retinopathy and laser-induced choroidal neovascularisation [17,18].…”

The urokinase‐type plasminogen activator system as drug target in retinitis pigmentosa: New pre‐clinical evidence in the rd10 mouse model

“…Each histogram represents the mean ± SEM of data from six independent samples angiogenesis and inflammation. 5 In the diseased retina, the inhibition of the uPA system has been shown to block critical processes involved in both angiogenesis and inflammation, 14,15,19,20 showing that, in respect to WT mice, the levels of HIF-1α, VEGF, uPA and uPAR were lower in rd10 mice either normoxic or subjected to the oxygeninduced retinopathy (OIR) protocol. After HIF-1α stabilization with intravitreal dimethyloxalylglycine (DMOG), the levels of HIF-1α, VEGF, uPA and uPAR were higher than those in mice intravitreally injected with vehicle (*P < 0.001 vs respective WT; § P < 0.001 vs vehicletreated rd10; One-way ANOVA followed by Newman-Keuls' multiple comparison post-test).…”