MicroRNA-148a/b-3p regulates angiogenesis by targeting neuropilin-1 in endothelial cells

MicroRNAs (miRs) are crucial regulators of vascular endothelial cell (EC) functions, including migration, proliferation, and survival. However, the role of most miRs in ECs remains unknown. Using RNA sequencing analysis, we found that miR-148a/b-3p expression was significantly downregulated during the differentiation of umbilical cord blood mononuclear cells into outgrowing ECs and that decreased miR-148a/b-3p levels were closely related to EC behavior. Overexpression of miR-148a/b-3p in ECs significantly reduced migration, filamentous actin remodeling, and angiogenic sprouting. Intriguingly, the effects of decreased miR-148a/b-3p levels were augmented by treatment with vascular endothelial growth factor (VEGF). Importantly, we found that miR-148a/b-3p directly regulated neuropilin-1 (NRP1) expression by binding to its 3′-untranslated region. In addition, because NRP1 is the coreceptor for VEGF receptor 2 (VEGFR2), overexpression of miR-148a/b-3p inhibited VEGF-induced activation of VEGFR2 and inhibited its downstream pathways, as indicated by changes to phosphorylated focal adhesion kinase (FAK), extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase. Collectively, our results demonstrate that miR-148a/b-3p is a direct transcriptional regulator of NRP1 that mediates antiangiogenic pathways. These data suggest that miR-148a/b-3p is a therapeutic candidate for overcoming EC dysfunction and angiogenic disorders, including ischemia, retinopathy, and tumor vascularization.
Vascular biology: MicroRNA implicated in blood vessel formation A small regulatory RNA molecule helps prevent the development of new blood vessels, a finding that could have implications for the treatment of vascular disease and cancer. Young-Guen Kwon from Yonsei University in Seoul, South Korea, and colleagues cataloged all the microRNAs expressed during the differentiation of umbilical cord blood stem cells into precursors of the cells that line the inside of blood vessels. One microRNA in particular stood out for its association with cellular differentiation. The authors showed that this microRNA, called miR-148a/b-3p, directly binds part of the gene transcript encoding neuropilin-1, thereby blocking the production of this receptor for growth factors involved in new blood vessel formation. Modulating the activity of miR-148a/b-3p could have therapeutic value for disorders marked by aberrant blood vessel growth.