BAT-derived miR-378a-3p facilitates endothelial angiogenic function and promotes wound healing
Hongyan Deng, Yuyu Xie, Jiadai Liu, Jing Ge, Qianqian Kang, Rui He, Zhihan Wang, Xuemin Peng, Zengzhe Zhu, Wenshe Wang, Yulian Liu, Ronghui Gao, Ruping Pan, Min Yang, Yong Chen
Hongyan Deng, Yuyu Xie, Jiadai Liu, Jing Ge, Qianqian Kang, Rui He, Zhihan Wang, Xuemin Peng, Zengzhe Zhu, Wenshe Wang, Yulian Liu, Ronghui Gao, Ruping Pan, Min Yang, Yong Chen
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Research Article Metabolism Vascular biology

BAT-derived miR-378a-3p facilitates endothelial angiogenic function and promotes wound healing

Abstract

Interscapular brown adipose tissue (BAT), one of the most vascularized tissues in the body, exemplifies the intricate crosstalk between the vascular system and adipocytes. BAT is known to secrete abundant exosomes into circulation, and exosomes are known to play a key role in vascular remodeling and cell migration. However, whether BAT-derived exosomes (BATexos) modulate peripheral vasculature remains unclear. Here, we report that BATexos promoted peripheral angiogenesis and vascular repair. Among their cargo, miR-378a-3p was highly enriched and identified as a key mediator of endothelial angiogenic function. The overexpression of miR-378a-3p in endothelial cells substantially promoted cell migration and tube formation. Conversely, inhibition of exosome secretion from BAT impaired vascular repair and delayed wound healing. Mechanistically, miR-378a-3p directly targeted the phosphatase and tensin homolog (Pten), thereby activating the PI3K/AKT signaling pathway. Liposomes encapsulating miR-378 mimics promoted angiogenesis and accelerated wound healing in a diabetic mouse model. Collectively, this study uncovers BAT-derived miR-378a-3p as a key regulator of vessel regeneration and tissue repair after injury, offering therapeutic potential for treating vascular complications in metabolic disease.

Authors

Hongyan Deng, Yuyu Xie, Jiadai Liu, Jing Ge, Qianqian Kang, Rui He, Zhihan Wang, Xuemin Peng, Zengzhe Zhu, Wenshe Wang, Yulian Liu, Ronghui Gao, Ruping Pan, Min Yang, Yong Chen

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Figure 6

miR-378a-3p enhances endothelial angiogenic function by targeting Pten and activating the PI3K/AKT signaling pathway.

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miR-378a-3p enhances endothelial angiogenic function by targeting Pten a...
(A) qPCR analysis of miR-378a-3p level (n = 3). (B) Schematic of RNA-Seq results for ECs overexpressing miR-378a-3p. (C) GO analysis of genes upregulated in ECs after overexpressing miR-378a-3p. (D) The intersection of the predicted results in the miRWalk database, the DIANA database, the TarBase database, and angiogenesis-related genes. (E) qPCR analysis of candidate target genes in ECs. (F) Western blot analysis of PTEN, NUFIP2, and PI3K p110α in ECs treated with miR-control and miR-378a-3p (n = 3). Right: quantification of the data. (G) Schematic illustration of the predicted binding site and corresponding mutation site between the miR-378a-3p and Pten 3′UTR. (H) Results of dual-luciferase reporter experiments (n = 3). (I) Representative images of tube formation in ECs transfected with miR-control, miR-378 mimic, or miR-378 mimic plus PTEN overexpression plasmid (n = 4). Scale bar: 200 μm. The corresponding quantitative analysis of junction number and tube length is displayed on the bottom. (J) Protein levels of p-AKT, AKT, p-PI3K, and PI3K in ECs under 4 conditions: miR-control, miR-378a-3p overexpression, Akt inhibitor (MK2206) treatment, and combined miR-378a-3p overexpression with MK2206 treatment. Quantification of p-AKT/AKT and p-PI3K/PI3K levels in ECs of 4 groups (n = 3) (right). (K) Scratch assays were used to assess the migration of ECs overexpressing miR-378a-3p or treated with the Akt inhibitor MK2206 (n = 5). Scale bar: 500 μm. The corresponding statistical analysis of migration rate is displayed on the right. The value n represents the number of biologically independent samples, from which all experimental data were obtained. Statistical analysis was performed using 2-tailed Student’s t test (A, F, and H) or 1-way ANOVA with Tukey’s multiple-comparison test (I–K). The data are expressed as mean ± SEM. NS = not significant, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.