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

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posted on 2025-01-24, 17:43 authored by Tingting Zeng, Kan Sun, Lifang Mai, Xiaosi Hong, Xiaodan He, Weijie Lin, Sifan Chen, Li Yan

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.

Funding

This study was supported by the National Natural Science Foundation of China (82200902); Guangdong Clinical Research Center for Metabolic Diseases (2020B1111170009); and Guangzhou Key Laboratory for Metabolic Diseases (202102100004); The National Natural Science Foundation of China Excellent Young Scientists Fund (82222014); The National Natural Science Foundation of China (32271185), Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, China; and Guangzhou Science and Technology Program (2023A03J0706).

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