Extracellular vesicle-associated miR-ERIA exerts the anti-angiogenic effect of macrophages in diabetic wound healing

IF 7.5 1区医学 Q1 ENDOCRINOLOGY & METABOLISM Diabetes Pub Date : 2025-01-24 DOI:10.2337/db24-0701

Tingting Zeng, Kan Sun, Lifang Mai, Xiaosi Hong, Xiaodan He, Weijie Lin, Sifan Chen, Li Yan

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Abstract

Many cell types are involved in the regulation of cutaneous wound healing in diabetes. Clarifying the mechanism of cell-cell interactions is important for identifying therapeutic targets for diabetic cutaneous ulcers. The function of vascular endothelial cells in the cutaneous microenvironment is critical, and a decrease in their biological function leads directly to refractory wound healing. In this study, we aimed to study the interactions of macrophages with vascular endothelial cells and elucidate the mechanism of diabetic wound angiogenesis suppression. We found that macrophages polarized to the M1 type, inhibited the migration and tube formation of human umbilical vein endothelial cells (HUVECs) by secreting extracellular vesicles after treatment with advanced glycation end products (AGEs-EVs), and contributed to wound angiogenesis and delayed wound healing in vivo. Mechanistically, we identified a novel miRNA enriched in AGEs-EVs, namely miR-ERIA, that suppress the biological function of HUVECs by targeting helicase with zinc finger 2 (HELZ2), and in vivo experiments showed that miR-ERIA suppression could promote wound angiogenesis and thus accelerate wound healing in diabetes. We found that miR-ERIA regulates diabetic wound angiogenesis by targeting HELZ2, suggesting a potential therapeutic target for diabetic foot ulcers.

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细胞外囊泡相关的miR-ERIA在糖尿病创面愈合中发挥巨噬细胞的抗血管生成作用

许多细胞类型参与糖尿病皮肤伤口愈合的调节。阐明细胞间相互作用的机制对于确定糖尿病性皮肤溃疡的治疗靶点至关重要。血管内皮细胞在皮肤微环境中的功能是至关重要的，其生物功能的下降直接导致难治性伤口愈合。在本研究中，我们旨在研究巨噬细胞与血管内皮细胞的相互作用，阐明糖尿病创面血管生成抑制的机制。我们发现巨噬细胞极化为M1型，在接受晚期糖基化终产物（ages - ev）治疗后，通过分泌细胞外囊泡抑制人脐静脉内皮细胞（HUVECs）的迁移和管状形成，并有助于体内伤口血管生成和延迟伤口愈合。在机制上，我们发现了一种富含ages - ev的新型miRNA，即miR-ERIA，它通过靶向锌指2 （HELZ2）的螺旋酶来抑制HUVECs的生物学功能，体内实验表明，抑制miR-ERIA可以促进伤口血管生成，从而加速糖尿病伤口愈合。我们发现miR-ERIA通过靶向HELZ2调节糖尿病创面血管生成，提示糖尿病足溃疡的潜在治疗靶点。

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.