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Endothelium-derived semaphorin 3G attenuates ischemic retinopathy by coordinating β-catenin–dependent vascular remodeling
Dan-Yang Chen, … , Ying-Mei Lu, Feng Han
Dan-Yang Chen, … , Ying-Mei Lu, Feng Han
Published February 15, 2021
Citation Information: J Clin Invest. 2021;131(4):e135296. https://doi.org/10.1172/JCI135296.
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Research Article Vascular biology

Endothelium-derived semaphorin 3G attenuates ischemic retinopathy by coordinating β-catenin–dependent vascular remodeling

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Abstract

Abnormal angiogenesis and regression of the diseased retinal vasculature are key processes associated with ischemic retinopathies, but the underlying mechanisms that regulate vascular remodeling remain poorly understood. Here, we confirmed the specific expression of semaphorin 3G (Sema3G) in retinal endothelial cells (ECs), which was required for vascular remodeling and the amelioration of ischemic retinopathy. We found that Sema3G was elevated in the vitreous fluid of patients with proliferative diabetic retinopathy (PDR) and in the neovascularization regression phase of oxygen-induced retinopathy (OIR). Endothelial-specific Sema3G knockout mice exhibited decreased vessel density and excessive matrix deposition in the retinal vasculature. Moreover, loss of Sema3G aggravated pathological angiogenesis in mice with OIR. Mechanistically, we demonstrated that HIF-2α directly regulated Sema3G transcription in ECs under hypoxia. Sema3G coordinated the functional interaction between β-catenin and VE-cadherin by increasing β-catenin stability in the endothelium through the neuropilin-2 (Nrp2)/PlexinD1 receptor. Furthermore, Sema3G supplementation enhanced healthy vascular network formation and promoted diseased vasculature regression during blood vessel remodeling. Overall, we deciphered the endothelium-derived Sema3G-dependent events involved in modulating physiological vascular remodeling and regression of pathological blood vessels for reparative vascular regeneration. Our findings shed light on the protective effect of Sema3G in ischemic retinopathies.

Authors

Dan-Yang Chen, Ning-He Sun, Xiang Chen, Jun-Jie Gong, Song-Tao Yuan, Zi-Zhong Hu, Nan-Nan Lu, Jakob Körbelin, Kohji Fukunaga, Qing-Huai Liu, Ying-Mei Lu, Feng Han

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Figure 12

PlexinD1 is necessary for the functional performance of endothelial Sema3G against pathological neovascularization.

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PlexinD1 is necessary for the functional performance of endothelial Sema...
(A) Schematic diagram of the AAV used for PlexinD1 knockdown in vivo. (B) Transduction of ECs with AAV in Cdh5-Cre Sema3Gfl/fl OIR mice. Neonatal mice were injected through the retro-orbital sinus with AAV at P7 and P12. At P17, mouse pups were intravitreally injected with 1 μg IgG or recombinant Sema3G. Retinas were analyzed at P19. (C) Representative images of RNA in situ hybridization for PlexinD1 mRNA in whole-mounted retinas of OIR mice. (D) Quantification of PlexinD1 mRNA in OIR retinas in C (n = 4 mice for each group). (E) IB4 staining of retinas from Cdh5-Cre Sema3Gfl/fl OIR mice transduced with AAV-shControl or AAV-shPlexinD1 and treated with or without recombinant Sema3G protein. (F and G) Quantification of the avascular area and NVT area at P19 in OIR, related to E (n = 9, 10, 8, and 10 mice for Cdh5-Cre Sema3Gfl/fl + AAV-shControl + IgG, Cdh5-Cre Sema3Gfl/fl + AAV-shControl + Sema3G, Cdh5-Cre Sema3Gfl/fl + AAV-shPlexinD1+ IgG and Cdh5-Cre Sema3Gfl/fl + AAV-shPlexinD1 + Sema3G groups, respectively). Error bars represent mean ± SEM. **P < 0.01; ***P < 0.001; 2-tailed Student’s t tests (D) and 1-way ANOVA with Tukey’s multiple comparisons test (F and G). Scale bars: 50 μm (C) and 1000 μm (E).

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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