Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany; and.
Department of Oncology, Fudan University Shanghai Cancer Center-Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
FASEB J. 2019 Jun;33(6):7213-7224. doi: 10.1096/fj.201802085RR. Epub 2019 Mar 13.
MicroRNAs (miRNAs) crucially modulate fundamental biologic processes such as angiogenesis. In the present study, we focused on the molecular function of miRNA-370-3p (miR-370) in regulating the angiogenic activity of endothelial cells (ECs). Transfection with miR-370 mimic (miR-370m) significantly inhibited the sprouting of human dermal microvascular EC (HDMEC) and HUVEC spheroids and mouse aortic rings, whereas miR-370 inhibitor (miR-370i) promoted sprout formation. Additional assays demonstrated the pleiotropic inhibitory effects of miR-370m on HDMEC proliferation, migration, and tube formation. Moreover, Matrigel plugs containing miR-370m-transfected HDMECs exhibited a reduced microvessel density after implantation into CD1 nude mice when compared with controls. In contrast, miR-370i exerted proangiogenic effects. Mechanistic analyses revealed that miR-370 directly targets smoothened (SMO) and down-regulates bone morphogenetic protein (BMP)-2 expression in HDMECs. Accordingly, inhibition of SMO by cyclopamine reversed miR-370i-induced HDMEC proliferation and migration. In addition, BMP-2 treatment counteracted miR-370m-suppressed tube formation of HDMECs, whereas blockade of BMP-2 with neutralizing antibody significantly inhibited miR-370i-induced tube formation. Taken together, these novel findings indicate that miR-370 is a potent inhibitor of angiogenesis, which directly targets SMO and BMP-2.-Gu, Y., Becker, V., Zhao, Y., Menger, M. D., Laschke, M. W. miR-370 inhibits the angiogenic activity of endothelial cells by targeting smoothened (SMO) and bone morphogenetic protein (BMP)-2.
微小 RNA（miRNAs）在调节血管生成等基本生物学过程中起着至关重要的作用。在本研究中，我们专注于 miRNA-370-3p（miR-370）在调节内皮细胞（EC）血管生成活性方面的分子功能。miR-370 模拟物（miR-370m）转染显著抑制了人真皮微血管内皮细胞（HDMEC）和 HUVEC 球体以及小鼠主动脉环的发芽，而 miR-370 抑制剂（miR-370i）则促进了芽的形成。其他实验进一步证明了 miR-370m 对 HDMEC 增殖、迁移和管形成的多效抑制作用。此外，与对照组相比，植入 CD1 裸鼠后，含有转染 miR-370m 的 HDMEC 的 Matrigel 塞显示出较低的微血管密度。相比之下，miR-370i 发挥了促血管生成作用。机制分析表明，miR-370 直接靶向 smoothened（SMO）并下调 HDMEC 中的骨形态发生蛋白（BMP）-2 表达。因此，用 cyclopamine 抑制 SMO 逆转了 miR-370i 诱导的 HDMEC 增殖和迁移。此外，BMP-2 处理抵消了 miR-370m 抑制 HDMEC 管形成的作用，而用中和抗体阻断 BMP-2 则显著抑制了 miR-370i 诱导的管形成。总之，这些新发现表明，miR-370 是血管生成的有效抑制剂，其直接靶向 SMO 和 BMP-2。
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