Transforming Growth Factor-β Inhibition Decreases Diode Laser–Induced Choroidal Neovascularization Development in Rats: P17 and P144 Peptides

Recalde, Sergio; Zarranz‐Ventura, Javier; Fernández-Robredo, Patricia; García-Gómez, P.J.; Salinas-Alamán, Angel; Borrás‐Cuesta, Francisco; Dotor, Javier; García‐Layana, Alfredo

doi:10.1167/iovs.11-7300

Cited by 24 publications

(27 citation statements)

References 40 publications

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“…This may be based on its role in supressing the stalk-cell phenotype in endothelial tip-cells via the modulation of Alk1 and Alk5 mediated TGFB superfamily signalling [26]. In a pathological context, we have previously demonstrated that inhibition of TGFB can reduce CNV lesion size in the laser-induced CNV model [35–37]. This confirms that blocking of not only VEGF but also of other targets can be effective in preventing CNV.…”

Section: Discussionmentioning

confidence: 72%

Neuropilin 1 Involvement in Choroidal and Retinal Neovascularisation

et al. 2017

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PurposeInhibiting VEGF is the gold standard treatment for neovascular age-related macular degeneration (AMD). It is also effective in preventing retinal oedema and neovascularisation (NV) in diabetic retinopathy (DR) and retinal vein occlusions (RVO). Neuropilin 1 (Nrp1) is a co-receptor for VEGF and many other growth factors, and therefore a possible alternative drug target in intra ocular neovascular disease. Here we assessed choroidal and retinal NV in an inducible, endothelial specific knock out model for Nrp1.MethodsCrossing Nrp1 floxed mice with Pdgfb-CreERT2 mice produced tamoxifen-inducible, endothelial specific Nrp1 knock out mice (Nrp1ΔEC) and Cre-negative, control littermates. Cre-recombinase activity was confirmed in the Ai3(RCL-EYFP) reporter strain. Animals were subjected to laser-induced CNV (532 nm) and spectral domain-optical coherence tomography (SD-OCT) was performed immediately after laser and at day 7. Fluorescein angiography (FA) evaluated leakage and postmortem lectin staining in flat mounted RPE/choroid complexes was also used to measure CNV. Furthermore, retinal neovascularisation in the oxygen induced retinopathy (OIR) model was assessed by immunohistochemistry in retinal flatmounts.ResultsIn vivo FA, OCT and post-mortem lectin staining showed a statistically significant reduction in leakage (p<0.05), CNV volume (p<0.05) and CNV area (p<0.05) in the Nrp1ΔEC mice compared to their Cre-negative littermates. Also the OIR model showed reduced retinal NV in the mutant animals compared to wild types (p<0.001).ConclusionWe have demonstrated reduced choroidal and retinal NV in animals that lack endothelial Nrp1, confirming a role of Nrp1 in those processes. Therefore, Nrp1 may be a promising drug target for neovascular diseases in the eye.

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Section: Discussionmentioning

confidence: 72%

Neuropilin 1 Involvement in Choroidal and Retinal Neovascularisation

et al. 2017

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“…Nagineni et al [30] demonstrated that TGF-β can induce the secretion of VEGF from the retinal pigment epithelium (RPE) and choroidal cells, and play an important role in CNV in AMD. Two weeks after laser-induced CNV in rats, Zarranz-Ventura et al [31] confirmed that inhibition of TGF-β can reduce the progression of CNV lesions, and Recalde et al [32] drew a similar conclusion. Yuan and Neufeld [38] found that whereas microglial cells do not express TGF-β 2 in normal optic nerve heads and rarely contain TGF-β 1 , they can express TGF-β 2 in glaucomatous optic nerve heads, and a few of them contain TGF-β 1 .…”

Section: Discussionmentioning

confidence: 88%

“…Apart from VEGF, other pro-angiogenic factors like PDGF-β [17,24,25] , FGF [26][27][28][29] , TGF-β [17,[29][30][31][32] , and IL-8 [33][34][35][36] were also reported to be involved in the pathological process of AMD. Zehetner et al [24] compared the plasma levels of PDGF-β in neovascular AMD patients with healthy controls and found that there was a significantly higher plasma PDGF-β level in neovascular AMD patients than in healthy controls.…”

Section: Discussionmentioning

confidence: 99%

Behaviour of CD11b-Positive Cells in an Animal Model of Laser-Induced Choroidal Neovascularisation

Heiduschka

Alex

et al. 2017

Ophthalmologica

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Background/Aim: Immune cells, e.g. microglial cells of the retina, appear to be involved in pathological processes in neovascular age-related macular degeneration. Therefore, the purpose of this study was to immunohistochemically check the expression of various factors and cytokines by CD11b-positive (CD11b+) immune cells in an animal model of choroidal neovascularisation (CNV). Methods: We used the animal model of laser-induced CNV in mice. Eyes were isolated at 1, 4, 7, and 14 days after laser treatment. Cryosections were prepared and checked immunohistochemically for the presence of different growth factors and cytokines on microglial cells and other immune cells identified by CD11b immunoreactivity. Results: We found that the number of CD11b+ cells at the laser spots increased dramatically 4 days after laser treatment, the majority of them entering the laser spot most probably by migration. CD11b+ cells in the laser spot were positive for a variety of pro-angiogenic factors, such as PDGF-β, FGF-1, FGF-2, and TGF-β₁. They were also positive for some inflammatory cytokines, in particular TNF-α, IL-6, and CXCL1. In non-treated retinas, CD11b+ cells showed almost no immunoreactivity for these proteins. Conclusion: Microglial cells, macrophages, and other CD11b+ cells may promote the neovascularisation in the laser spot and show a moderate inflammatory behaviour. Immunoreactivity for most of these molecules was found to decrease during the time of observation. Modulation of immune cell activity may thus be a tool to reduce the extent of CNV.

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“…A synergistic association with b-FGF and tumor necrosis factor-alpha (TNF-α) over VEGF transcription has been reported, suggesting that TGF-β may work in concert with other cytokines in VEGF upregulation [19]. These findings led us to speculate that selective blockade of TGF-β would abate CNV development, a hypothesis recently confirmed in a study performed with two anti-TGF-β inhibitor peptides in a laser induced CNV model [20]. In this study, we evaluated the effect of these peptides on CNV induction, with treatments administered 48 hours after laser application.…”

Section: Introductionmentioning

confidence: 82%

Transforming Growth Factor-Beta Inhibition Reduces Progression of Early Choroidal Neovascularization Lesions in Rats: P17 and P144 Peptides

et al. 2013

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The purpose of this study was to assess the effects of transforming growth factor beta (TGF-β) inhibitor peptides (P17 & P144) on early laser-induced choroidal neovascularization (LI-CNV) lesions in rats, two weeks after laser CNV induction. Seventy-one Long Evans rats underwent diode laser application in an established LI-CNV model. Baseline fluorescein angiography (FA) was performed 14 days following laser procedure, and treatments were administered 16 days post-laser application via different administration routes. Intravenous groups included control (IV-Control), P17 (IV-17), and P144 (IV-144) groups, whereas intravitreal groups included P17 (IVT-17), P144 (IVT-144), and a mixture of both peptides (IVT-17+144) (with fellow eyes receiving vehicle alone). CNV evolution was assessed using FA performed weekly for four weeks after treatment. Following sacrifice, VEGF, TGF-β, COX-2, IGF-1, PAI-1, IL-6, MMP-2, MMP-9, and TNF-α gene expression was assessed using RT-PCR. VEGF and p-SMAD2 protein levels were also assessed by western-blot, while MMP-2 activity was assessed with gelatin zymography. Regarding the FA analysis, the mean CNV area was lower from the 3rd week in IVT-17 and IVT-144 groups, and also from the 2nd week in IVT-17+144. Biochemical analysis revealed that gene expression was lower for VEGF and COX-2 genes in IV-17 and IV-144 groups, VEGF gene in IVT-17+144 group and MMP-2 gene in IVT-17 and IVT-144 groups. VEGF protein expression was also decreased in IV-17, IV-144, IVT-17 and IVT-144, whereas pSMAD-2 levels were lower in IV-17, IV-144 and IVT-17+144 groups. Zymogram analysis revealed decreased MMP-2 activity in IV-17, IV-144, IVT-17 and IVT-144 groups. These data suggest that the use of TGF-β inhibitor peptides (P17 & P144) decrease the development of early CNV lesions by targeting different mediators than those typically affected using current anti-angiogenic therapies. Its potential role in the treatment of early CNV appears promising as a single therapy or adjuvant to anti-VEGF drugs.

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Transforming Growth Factor-β Inhibition Decreases Diode Laser–Induced Choroidal Neovascularization Development in Rats: P17 and P144 Peptides

Abstract: TGF-β inhibition with these peptides represents a promising new therapeutic line for CNV targeting a different pathway than current therapies. More studies are needed to assess this effect on early CNV, alone or in combination with anti-VEGF.

Cited by 24 publications

References 40 publications

Neuropilin 1 Involvement in Choroidal and Retinal Neovascularisation

Neuropilin 1 Involvement in Choroidal and Retinal Neovascularisation

Behaviour of CD11b-Positive Cells in an Animal Model of Laser-Induced Choroidal Neovascularisation

Transforming Growth Factor-Beta Inhibition Reduces Progression of Early Choroidal Neovascularization Lesions in Rats: P17 and P144 Peptides

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