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MiR-181b suppresses angiogenesis by directly targeting cellular communication network factor 1

Abstract

Angiogenesis is essential for various physiological and pathological processes. Previous studies have shown that miRNAs play an important role in blood vessel development and angiogenesis. Recent studies have suggested that miR-181b might be involved in the regulation of angiogenesis in tumors. However, whether miR-181b plays a role in angiogenesis in nontumor diseases is unclear. We found that miR-181b expression was downregulated in hypoxia-stimulated primary human umbilical vein endothelial cells (HUVECs) and a mouse hindlimb ischemia (HLI) model. Gain- and loss-of-function studies showed that a miR-181b mimic inhibited HUVEC migration and tube formation in vitro, and a miR-181b inhibitor had the opposite effects. In vivo, agomir-181b suppressed perfusion recovery in the HLI model and capillary density in a Matrigel plug assay, while perfusion recovery and capillary density were increased by injection of antagomir-181b. Mechanistically, we showed with a reporter assay that cellular communication network factor 1 (CCN1) was a direct target of miR-181b. Moreover, miR-181b suppressed angiogenesis at least in part by targeting CCN1 to inhibit the AMPK signaling pathway. Our research suggests that miR-181b suppresses angiogenesis by directly targeting CCN1, which provides new clues for pro-angiogenic treatment strategies.

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Fig. 1: miR-181b was altered in cellular stimulation and animal models.
Fig. 2: miR-181b inhibited endothelial angiogenesis in vitro.
Fig. 3: miR-181b hindered neovascularization in vivo.
Fig. 4: miR-181b directly targeted CCN1.
Fig. 5: CCN1 restored miR-181b-regulated phosphorylated AMPK expression and tube-like network formation.
Fig. 6: The expression of miR-181b and CCN1 in human gastrocnemius muscle.

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Funding

This study was funded by the Ministry of Science and Technology of China grant 2016 YFA0101100, the National Natural Science Foundation of China (No: 91949201 and No: 81830014) and Wuhan Science and Technology Plan Project (2018060401011328), and Natural Science Foundation of Hubei Province (2020CFB429).

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ML, JZ, and KH conceived and designed the experiments. YL and SF performed the experiments and prepared the paper. WX and BQ participated in discussions of data analysis. ML, JZ, and KH revised the paper. All the authors gave final approval.

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Correspondence to Kai Huang or Jingqun Zhou or Minglu Liang.

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Li, Y., Fan, S., Xia, W. et al. MiR-181b suppresses angiogenesis by directly targeting cellular communication network factor 1. Lab Invest (2021). https://doi.org/10.1038/s41374-021-00596-4

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