|ZFIN ID: ZDB-PUB-130927-36|
|Source:||Circulation research 113(11): 1231-41 (Journal)|
|Registered Authors:||MacRae, Calum A.|
|Keywords:||MicroRNA-26a, BMP/SMAD signaling, angiogenesis, microRNA, endothelial function, SMAD, myocardial infarction|
|PubMed:||24047927 Full text @ Circ. Res.|
Rationale: The rapid induction and orchestration of new blood vessels is critical for tissue repair in response to injury, such as myocardial infarction (MI), and for physiological angiogenic responses such as embryonic development and exercise.
Objective: We aimed to identify and characterize microRNAs that regulate pathological and physiological angiogenesis.
Methods and Results: We show that microRNA-26a (miR-26a) regulates pathological and physiological angiogenesis by targeting EC BMP/SMAD1 signaling in vitro and in vivo. MiR-26a expression is increased in a model of acute MI in mice and in human subjects with acute coronary syndromes. Ectopic expression of miR-26a markedly induced EC cycle arrest and inhibited EC migration, sprouting angiogenesis, and network tube formation in matrigel, whereas blockade of miR-26a had the opposite effects. Mechanistic studies demonstrate that miR-26a inhibits the BMP/SMAD1 signaling pathway in ECs by binding to the SMAD1 3'-UTR, an effect that decreased expression of Id1 and increased p21WAF/CIP and p27. In zebrafish, miR-26a overexpression inhibited formation of the caudal vein plexus, a BMP-responsive process, an effect rescued by ectopic SMAD1 expression. In mice, miR-26a overexpression inhibited EC SMAD1 expression and exercise-induced angiogenesis. Furthermore, systemic intravenous administration of an miR-26a inhibitor, LNA-antimiR-26a, increased SMAD1 expression and rapidly induced robust angiogenesis within two days, an effect associated with reduced myocardial infarct size and improved heart function.
Conclusions: These findings establish miR-26a as a regulator of BMP/SMAD1-mediated EC angiogenic responses and that manipulating miR-26a expression could provide a new target for rapid angiogenic therapy in ischemic disease states.