期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
卷 1823, 期 10, 页码 1925-1935出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2012.07.011
关键词
microRNA; Phosphoinositide-3-kinase; Angiopoietin-1; Endothelial cell
资金
- Associazione Italiana per la Ricerca sul Cancro (ARC) [10133, 9158]
- Fondazione Piemontese per la Ricerca sul Cancro-ONLUS [5x1000 2008]
- Regione Piemonte
- CRT Foundation
- Italian Ministry of Health
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 (p85 beta). Down-regulation of miR-126 and over-expression of p85 beta 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. (C) 2012 Elsevier B.V. All rights reserved.
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