The miR-126 regulates Angiopoietin-1 signaling and vessel maturation by targeting p85β

• Published in: Biochimica et biophysica acta 2012-10, Vol.1823 (10), p.1925-1935
• Main Authors: Sessa, Roberto, Seano, Giorgio, di Blasio, Laura, Gagliardi, Paolo Armando, Isella, Claudio, Medico, Enzo, Cotelli, Franco, Bussolino, Federico, Primo, Luca
• Format: Article
• Language: English
• Subjects: Angiopoietin-1; Angiopoietin-1 - genetics; Angiopoietin-1 - metabolism; Animals; Blood Vessels - embryology; Blood Vessels - metabolism; Cell Survival; Class Ia Phosphatidylinositol 3-Kinase - metabolism; Down-Regulation - genetics; Embryo, Nonmammalian - blood supply; Embryo, Nonmammalian - metabolism; Endothelial cell; Enzyme Activation; Gene Expression Regulation, Developmental; HeLa Cells; Human Umbilical Vein Endothelial Cells; Humans; In Vitro Techniques; Mice; microRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Morphogenesis; Neovascularization, Physiologic - genetics; Phosphoinositide-3-kinase; Proto-Oncogene Proteins c-akt - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - genetics; Zebrafish - embryology; Zebrafish - genetics; Zebrafish - metabolism
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2012.07.011

Blood vessel formation depends on the highly coordinated actions of a variety of angiogenic regulators. Vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1) are both potent and essential proangiogenic factors with complementary roles in vascular development and function. Whereas VEGF is required for the formation of the initial vascular plexus, Ang-1 contributes to the stabilization and maturation of growing blood vessels. Here, we provide evidence of a novel microRNA (miRNA)-dependent molecular mechanism of Ang-1 signalling modulation aimed at stabilizing adult vasculature. MiRNAs are short non-coding RNA molecules that post-trascriptionally regulate gene expression by translational suppression or in some instances by cleavage of the respective mRNA target. Our data indicate that endothelial cells of mature vessels express high levels of miR-126, which primarily targets phosphoinositide-3-kinase regulatory subunit 2 (p85β). Down-regulation of miR-126 and over-expression of p85β in endothelial cells inhibit the biological functions of Ang-1. Additionally, knockdown of miR-126 in zebrafish resulted in vascular remodelling and maturation defects, reminiscent of the Ang-1 loss-of-function phenotype. Our findings suggest that miR-126-mediated phosphoinositide-3-kinase regulation, not only fine-tunes VEGF-signaling, but it strongly enhances the activities of Ang-1 on vessel stabilization and maturation. ► Mature blood vessels express high levels of miR-126. ► Endothelial miR-126 targets the PI3K regulatory subunit 2 (p85β). ► High levels of p85β inhibit endothelial cells survival and sprouting induced by Ang1.