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

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 2

Sema3G is elevated in the vitreous of patients suffering from PDR.

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Sema3G is elevated in the vitreous of patients suffering from PDR. (A) A...
(A) Angiography and SD-OCT were obtained from patients. Nonvascular ocular pathologies patients served as controls. Scale bars: 2000 μm (top), 500 μm (center). (B) ELISA assessment of vitreous fluid shows induction in Sema3G, IL-8, and VEGFA. The results are expressed as the absolute concentrations compared with control patients (n = 10 samples). (C and D) Immunoblot analysis and quantification of Sema3G protein levels in equal volumes of vitreous fluid from patients (n = 3 samples for each group). (E and F) Immunoblot analysis and quantification of Sema3G protein levels in equal volumes of aqueous humor from patients with PDR without DME, PDR with DME, and DME only (n = 3 samples for each group). Nondiabetic patients undergoing cataract surgery served as controls. (G) RNA in situ hybridization for Sema3G mRNA and immunofluorescence for lectin (an EC marker) in fibrovascular membranes (FVMs) of patients suffering from PDR. Error bars represent mean ± SEM, *P < 0.05; **P < 0.01; 2-tailed Student’s t tests (B and D), 1-way ANOVA with Tukey’s multiple comparisons test (F). Scale bar: 50 μm (G).