Notch activation promotes endothelial quiescence by repressing MYC expression via miR-218

作者：Sun, Jia-Xing; Dou, Guo-Rui; Yang, Zi-Yan; Liang, Liang; Duan, Juan-Li; Ruan, Bai; Li, Man-Hong; Chang, Tian-Fang; Xu, Xin-Yuan; Chen, Juan-Juan; Wang, Yu-Sheng^*; Yan, Xian-Chun^*; Han, Hua^*

来源：Molecular Therapy-Nucleic Acids, 2021, 25: 554-566.

DOI：10.1016/j.omtn.2021.07.023

• C-MYC
• TUMOR ANGIOGENESIS
• CYCLIN D1
• HOMEOSTASIS
• RECEPTORS

After angiogenesis-activated embryonic and early postnatal vascularization, endothelial cells (ECs) in most tissues enter a quiescent state necessary for proper tissue perfusion and EC functions. Notch signaling is essential for maintaining EC quiescence, but the mechanisms of action remain elusive. Here, we show that microRNA-218 (miR-218) is a downstream effector of Notch in quiescent ECs. Notch activation upregulated, while Notch blockade downregulated, miR-218 and its host gene Slit2, likely via transactivation of the Slit2 promoter. Overexpressing miR-218 in human umbilical vein ECs (HUVECs) significantly repressed cell proliferation and sprouting in vitro. Transcriptomics showed that miR-218 overexpression attenuated the MYC proto-oncogene, bHLH transcription factor (MYC, also known as c-myc) signature. MYC overexpression rescued miR-218-mediated proliferation and sprouting defects in HUVECs. MYC was repressed by miR-218 via multiple mechanisms, including reduction of MYC mRNA, repression of MYC translation by targeting heterogeneous nuclear ribonucleoprotein Al (hnRNPA1), and promoting MYC degradation by targeting EYA3. Inhibition of miR-218 partially reversed Notch-induced repression of HUVEC proliferation and sprouting. In vivo, intravitreal injection of miR-218 reduced retinal EC proliferation accompanied by MYC repression, attenuated pathological choroidal neovascularization, and rescued retinal EC hyper-sprouting induced by Notch blockade. In summary, miR-218 mediates the effect of Notch activation of EC quiescence via MYC and is a potential treatment for angiogenesis-related diseases.

• 单位
  中国人民解放军第四军医大学; 南方医科大学