Abstract
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.
Highlights
In vivo Fluorescein angiography (FA), OCT and post-mortem lectin staining showed a statistically significant reduction in leakage (p
We have demonstrated reduced choroidal and retinal NV in animals that lack endothelial Neuropilin 1 (Nrp1), confirming a role of Nrp1 in those processes
A final common complication for multiple retinal diseases, such as age related macular degeneration (AMD), diabetic retinopathy (DR) and retinal vein occlusions (RVO) is the growth of abnormal neovascular blood vessels with increased permeability that produce fluid leakage in the macula [1,2], which can lead to vision loss
Summary
Data Availability Statement: All relevant data are within the paper. Crossing Nrp floxed mice with Pdgfb-CreERT2 mice produced tamoxifen-inducible, endothelial specific Nrp knock out mice (Nrp1ΔEC) and Cre-negative, control littermates. 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 used to measure CNV. Retinal neovascularisation in the oxygen induced retinopathy (OIR) model was assessed by immunohistochemistry in retinal flatmounts
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