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Abstract：
BACKGROUND: 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.
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.
摘要：
在增殖性糖尿病视网膜病变（PDR）中的诱导，视网膜新生血管形成是与高葡萄糖（HG）诱导的内皮-间质转化（EndoMT）相关的重要致病过程。这种病理生理过程可能受G蛋白偶联的化学引诱物受体FPR2（小鼠FPR2）的调节，参与炎症细胞迁移和增殖。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（NG）或HG的人微血管内皮细胞（HMEC）中。形态学,表型，评估了HMEC的功能变化以及与EndoMT相关的微血管的形成。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,这引发了形态学变化，细胞获得了间充质表型，随着细胞迁移的增强，通过管形成和主动脉环发芽显示的活力和血管生成过程。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HMECEndoMT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中检测到间充质标志物的表达增加。FPR2缺乏与糖尿病小鼠视网膜中EndoMT相关的表型改变减少有关。结论FPR2积极参与EndoMT的进展，可能与PDR的发病有关。因此，FPR2可能是PDR的潜在治疗靶标。
