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 5

Endothelial Sema3G contributes to the coordination of vascular remodeling.

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Endothelial Sema3G contributes to the coordination of vascular remodelin...
(A) Representative images showing increased empty collagen IV–positive (green) but IB4-negative (magenta) matrix sleeves (yellow arrowheads) at the angiogenic front and in remodeling plexus of P6 Cdh5-Cre Sema3Gfl/fl mice. (B) Quantification of the ratio of IB4-positive vessels to collagen IV–positive vessels at the P6 angiogenic front (left, Sema3Gfl/fl, n = 7 mice; Cdh5-Cre Sema3Gfl/fl, n = 6 mice) and in remodeling plexus (right, n = 6 mice for each group). (C) Confocal images of anti–VE-cadherin–stained (green) and IB4-stained (red) (upper panel) or anti-desmin–stained (green) and IB4-stained (red) (lower panel) vascular plexus in P6 retinas. Arrowheads indicate EC-EC contacts with absent VE-cadherin signals. (D) Quantitation of vessel segments without a continuous junctional VE-cadherin signal (left, normalized to total IB4-labeled segments, n = 5 mice) and desmin-positive pericyte coverage in remodeling plexus (right, n = 4 mice). (E) Schematic illustration of the postnatal retinal angiogenesis model in Sema3Gfl/fl and Cdh5-Cre Sema3Gfl/fl mice. The postnatal retinal angiogenesis model could proceed as an overshooting reaction followed by the pruning of excessive vessels. Endothelial Sema3G deletion causes a hyperpruned vascular network in growing retinal vessels. Error bars represent mean ± SEM. *P < 0.05; **P < 0.01; 2-tailed Student’s t tests. Scale bars: 100 μm (A and C); magnified images: 50 μm (A and C).