miR‐370 inhibits the angiogenic activity of endothelial cells by targeting smoothened (SMO) and bone morphogenetic protein (BMP)‐2

ABSTRACT 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 in vitro 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. FASEB J. 33, 7213–7224 (2019). www.fasebj.org