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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 6

Endothelial Sema3G deficiency significantly delays the regression of pathological vasculature and inhibits vascular normalization in OIR retinas.

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Endothelial Sema3G deficiency significantly delays the regression of pat...
(A–H) IB4 staining of whole-mount retinas from Sema3Gfl/fl and Cdh5-Cre Sema3Gfl/fl OIR mice at P13 (A and E, n = 10 mice for each group), P15 (B and F, n = 8 mice for each group), P17 (C and G, n = 8 mice for each group), and P19 (D and H, n = 8 mice for each group) with quantification of the avascular area and neovascular tuft (NVT) area. The white dotted line indicates the edge of the retina, and the white area indicates NVTs. In the insets, the red line indicates the edge of the retina, the blue area indicates the avascular area, and the red area indicates NVTs. (I and J) TER119-positive RBC leakage and F4/80-positive macrophage infiltration in superficial and deep retinal layers of Sema3Gfl/fl OIR and Cdh5-Cre Sema3Gfl/fl OIR mice are shown. Error bars represent mean ± SEM. **P < 0.01; ***P < 0.001; 2-tailed Student’s t tests. Scale bars: 1000 μm (A–D) and 100 μm (I and J).

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

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