GBP2 inhibits pathological angiogenesis in the retina via the AKT/mTOR/VEGFA axis

IF 2.9 4区医学 Q2 PERIPHERAL VASCULAR DISEASE

Microvascular research Pub Date : 2024-04-16 DOI:10.1016/j.mvr.2024.104689

Xiaoxiang Xu , Xihui Ding , Zizhuo Wang , Shujiang Ye , Jianguang Xu , Zugang Liang , Renfei Luo , Jinyong Xu , Xiaohui Li , Zhenhua Ren

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引用次数: 0

Abstract

Pathological retinal angiogenesis is not only the hallmark of retinopathies, but also a major cause of blindness. Guanylate binding protein 2 (GBP2) has been reported to be associated with retinal diseases such as diabetic retinopathy and hypoxic retinopathy. However, GBP2-mediated pathological retinal angiogenesis remains largely unknown. The present study aimed to investigate the role of GBP2 in pathological retinal angiogenesis and its underlying molecular mechanism. In this study, we established oxygen-induced retinopathy (OIR) mice model for in vivo study and hypoxia-induced angiogenesis in ARPE-19 cells for in vitro study. We demonstrated that GBP2 expression was markedly downregulated in the retina of mice with OIR and ARPE-19 cells treated with hypoxia, which was associated with pathological retinal angiogenesis. The regulatory mechanism of GBP2 in ARPE-19 cells was studied by GBP2 silencing and overexpression. The regulatory mechanism of GBP2 in the retina was investigated by overexpressing GBP2 in the retina of OIR mice. Mechanistically, GBP2 downregulated the expression and secretion of vascular endothelial growth factor (VEGFA) in ARPE-19 cells and retina of OIR mice. Interestingly, overexpression of GBP2 significantly inhibited neovascularization in OIR mice, conditioned medium of GBP2 overexpressing ARPE-19 cells inhibited angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, we confirmed that GBP2 downregulated VEGFA expression and angiogenesis by inhibiting the AKT/mTOR signaling pathway. Taken together, we concluded that GBP2 inhibited pathological retinal angiogenesis via the AKT/mTOR/VEGFA axis, thereby suggesting that GBP2 may be a therapeutic target for pathological retinal angiogenesis.

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GBP2 通过 AKT/mTOR/VEGFA 轴抑制视网膜病理性血管生成。

病理性视网膜血管生成不仅是视网膜病变的标志，也是失明的主要原因。据报道，鸟苷酸结合蛋白 2（GBP2）与糖尿病视网膜病变和缺氧性视网膜病变等视网膜疾病有关。然而，GBP2 介导的病理性视网膜血管生成在很大程度上仍不为人所知。本研究旨在探讨 GBP2 在病理性视网膜血管生成中的作用及其潜在的分子机制。本研究建立了氧诱导视网膜病变（OIR）小鼠模型进行体内研究，并在ARPE-19细胞中进行缺氧诱导血管生成的体外研究。我们发现，在 OIR 小鼠视网膜和缺氧处理的 ARPE-19 细胞中，GBP2 表达明显下调，这与病理性视网膜血管生成有关。通过 GBP2 沉默和过表达研究了 GBP2 在 ARPE-19 细胞中的调控机制。通过在OIR小鼠视网膜中过表达GBP2，研究了GBP2在视网膜中的调控机制。从机制上讲，GBP2 下调了血管内皮生长因子（VEGFA）在 ARPE-19 细胞和 OIR 小鼠视网膜中的表达和分泌。有趣的是，过表达 GBP2 能显著抑制 OIR 小鼠的新生血管生成，过表达 GBP2 的 ARPE-19 细胞的条件培养基能抑制人脐静脉内皮细胞（HUVECs）的血管生成。此外，我们还证实，GBP2 通过抑制 AKT/mTOR 信号通路下调了 VEGFA 的表达和血管生成。综上所述，我们认为 GBP2 通过 AKT/mTOR/VEGFA 轴抑制了病理性视网膜血管生成，从而表明 GBP2 可能是病理性视网膜血管生成的治疗靶点。

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来源期刊

Microvascular research 医学-外周血管病

CiteScore

6.00

自引率

3.20%

发文量

158

审稿时长

43 days

期刊介绍： Microvascular Research is dedicated to the dissemination of fundamental information related to the microvascular field. Full-length articles presenting the results of original research and brief communications are featured. Research Areas include: • Angiogenesis • Biochemistry • Bioengineering • Biomathematics • Biophysics • Cancer • Circulatory homeostasis • Comparative physiology • Drug delivery • Neuropharmacology • Microvascular pathology • Rheology • Tissue Engineering.