G蛋白偶联的甲酰肽受体2促进糖尿病视网膜病变中的内皮-间充质转变。

IF 2 4区 医学 Q2 OPHTHALMOLOGY Ophthalmic Research Pub Date : 2023-01-01 Epub Date: 2023-02-20 DOI:10.1159/000529578
Xueying Lou, Shuang Liu, Jian Shi, Hongliang Chen, Zichen Wang, Yingying Le, Hui Chen, Rongrong Zhu, Ying Yu
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引用次数: 0

摘要

引言:在增殖性糖尿病视网膜病变(PDR)中,视网膜新生血管是与高糖(HG)诱导的内皮-间充质转化(EndoMT)有关的重要致病过程。这种病理生理过程可能受到G蛋白偶联的化学引诱剂受体FPR2(小鼠FPR2)的调节,该受体参与炎症细胞的迁移和增殖。在目前的研究中,我们研究了Fpr2在调节EndoMT中的作用以及糖尿病视网膜病变进展过程中的潜在机制。方法:将FPR2激动剂或抑制剂添加到暴露于正常葡萄糖或HG的人微血管内皮细胞(HMEC)中。对HMEC的形态学、表型和功能变化以及与EndoMT相关的微血管形成进行了评估。在糖尿病小鼠的视网膜组织和PDR患者的纤维血管视网膜前膜(FVM)中检测到EndoMT生物标志物。结果:HG上调HMEC中的FPR2,引发形态学变化,细胞获得间充质表型,细胞迁移、活力和血管生成过程增强,表现为管形成和主动脉环发芽。FPR2的抑制减弱了HG诱导的EndoMT和内皮细胞迁移以形成血管样管结构。RNA序列和蛋白质分析进一步表明,FPR2的抑制降低了与EndoMT相关的基因的表达。ERK1/2和P38信号通路在HMEC中被激活,促进HG诱导的HMEC的EndoMT中的新生血管形成。在体内,在糖尿病小鼠的视网膜和PDR患者的FVM中检测到间充质标记物的表达增加。FPR2缺乏与糖尿病小鼠视网膜中EndoMT相关表型变化减少有关。结论:FPR2积极参与EndoMT的进展,可能参与PDR的发病机制。因此,FPR2可能是PDR的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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The G-Protein-Coupled Formyl Peptide Receptor 2 Promotes Endothelial-Mesenchymal Transition in Diabetic Retinopathy.

Introduction: In proliferative diabetic retinopathy (PDR), retinal neovascularization is the essential pathogenic process that is linked to endothelial-to-mesenchymal transition (EndoMT) induced by high glucose (HG). This pathophysiological process may be regulated by a G-protein-coupled chemoattractant receptor FPR2 (mouse Fpr2), involved in inflammatory cell migration and proliferation. In the current study, we investigated the role of Fpr2 in regulating EndoMT and the underlying mechanisms during diabetic retinopathy progression.

Methods: FPR2 agonist or inhibitor was added to human microvascular endothelial cells (HMECs) exposed to normal glucose or HG. Morphologic, phenotypic, and functional changes of HMECs as well as the formation of microvasculature related to EndoMT were assessed. EndoMT biomarkers were detected in the retinal tissues of diabetic mice and fibrovascular epiretinal membranes (FVMs) from patients with PDR.

Results: HG upregulated FPR2 in HMECs, which triggered morphological changes, and the cells acquired mesenchymal phenotype, with enhanced cell migration, viability, and angiogenic process shown by tube formation and aortic ring sprouting. Inhibition of FPR2 attenuated HG-induced EndoMT and endothelial cell migration to form vessel-like tube structures. RNA sequence and protein analysis further revealed that inhibition of FPR2 decreased the expression of genes associated with EndoMT. ERK1/2 and P38 signaling pathway was activated in HMECs, promoting neovascularization in HG-induced EndoMT of HMECs. In vivo, increased expression of mesenchymal markers was detected in the retina of diabetic mice and FVMs from patients with PDR. FPR2 deficiency was associated with diminished EndoMT-related phenotypic changes in the retina of diabetic mice.

Conclusions: FPR2 is actively involved in the progression of EndoMT that may contribute to the pathogenesis of PDR. Thus, FPR2 may be a potential therapeutic target for PDR.

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来源期刊
Ophthalmic Research
Ophthalmic Research 医学-眼科学
CiteScore
3.80
自引率
4.80%
发文量
75
审稿时长
6-12 weeks
期刊介绍: ''Ophthalmic Research'' features original papers and reviews reporting on translational and clinical studies. Authors from throughout the world cover research topics on every field in connection with physical, physiologic, pharmacological, biochemical and molecular biological aspects of ophthalmology. This journal also aims to provide a record of international clinical research for both researchers and clinicians in ophthalmology. Finally, the transfer of information from fundamental research to clinical research and clinical practice is particularly welcome.
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