Endothelium-derived semaphorin 3G attenuates ischemic retinopathy by coordinating β-catenin-dependent vascular remodeling
Endothelium-derived semaphorin 3G attenuates ischemic retinopathy by coordinating β-catenin-dependent vascular remodeling
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DOI：
10.1172/jci135296
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发表时间：
2021-02-15
影响因子：
15.9
通讯作者：
Han, Feng
中科院分区：
文献类型：
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作者：
Chen, Dan-Yang;Sun, Ning-He;Han, Feng
异常血管生成和病变视网膜血管的消退是与缺血性视网膜病相关的关键过程，但调节血管重塑的潜在机制仍知之甚少。在此，我们证实了脑信号蛋白3G（Sema 3G）在视网膜内皮细胞（EC）中的特异性表达，这是血管重塑和缺血性视网膜病变改善所必需的。我们发现，在增殖性糖尿病视网膜病变（MR）患者的玻璃体液中，以及在氧诱导视网膜病变（OIR）的新生血管消退阶段，Sema 3G升高。内皮特异性Sema 3G基因敲除小鼠在视网膜血管系统中表现出血管密度降低和过度基质沉积。此外，Sema 3G的丢失加重了OIR小鼠的病理性血管生成。从机制上讲，我们证明了HIF-2 α直接调节缺氧条件下EC中Sema 3G的转录。Sema 3G通过神经纤毛蛋白-2（Nrp 2）/丛蛋白D1受体增加内皮细胞中β-连环蛋白的稳定性，协调β-连环蛋白和VE-钙粘蛋白之间的功能性相互作用。此外，补充Sema 3G增强了健康血管网络的形成，并促进了血管重塑过程中病变血管的消退。总的来说，我们破译了内皮源性Sema 3G依赖性事件参与调节生理性血管重塑和病理性血管的消退，用于修复性血管再生。我们的研究结果揭示了Sema 3G在缺血性视网膜病变中的保护作用。
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 (MR) 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-2 alpha directly regulated Sema3G transcription in ECs under hypoxia. Sema3G coordinated the functional interaction between beta-catenin and VE-cadherin by increasing beta-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.