MicroRNA-26a regulates pathological and physiological angiogenesis by targeting BMP/SMAD1 signaling.
MicroRNA-26a regulates pathological and physiological angiogenesis by targeting BMP/SMAD1 signaling.
复制标题
MicroRNA-26A通过靶向BMP/SMAD1信号来调节病理和生理血管生成。
DOI：
10.1161/circresaha.113.301780
复制
发表时间：
2013-11-08
影响因子：
20.1
通讯作者：
Feinberg MW
中科院分区：
文献类型：
--
作者：
Icli B;Wara AK;Moslehi J;Sun X;Plovie E;Cahill M;Marchini JF;Schissler A;Padera RF;Shi J;Cheng HW;Raghuram S;Arany Z;Liao R;Croce K;MacRae C;Feinberg MW
新血管的快速诱导和编排对于响应于损伤（例如心肌梗死）的组织修复以及对于生理性血管生成响应（例如胚胎发育和运动）是至关重要的。我们的目的是确定和表征微RNA（miR），调节病理和生理血管生成。我们发现miR-26 a通过靶向内皮细胞（EC）骨形态发生蛋白/SMAD 1信号转导在体外和体内调节病理和生理性血管生成。MiR-26 a表达在小鼠的急性心肌梗死模型和患有急性冠状动脉综合征的人类受试者中增加。miR-26 a的异位表达显著诱导EC周期停滞，并抑制EC迁移、出芽血管生成和基质胶中的网状管形成，而miR-26 a的阻断具有相反的效果。机制研究表明，miR-26 a通过与SMAD 1 3′-非翻译区结合，抑制内皮细胞中的骨形态发生蛋白/SMAD 1信号通路，从而降低Id 1的表达并增加p21 WAF/CIP和p27。在斑马鱼中，miR-26 a过表达抑制尾静脉丛的形成，这是一种骨形态发生蛋白反应过程，这种作用是由异位SMAD 1表达拯救的。在小鼠中，miR-26 a过表达抑制EC SMAD 1表达和运动诱导的血管生成。此外，全身静脉内给予miR-26 a抑制剂，锁核酸-抗miR-26 a，增加SMAD 1表达并在2天内快速诱导稳健的血管生成，这一效应与心肌梗死面积减少和心脏功能改善相关。这些发现确立了miR-26 a作为骨形态发生蛋白/SMAD 1介导的EC血管生成反应的调节剂，并且操纵miR-26 a表达可以为缺血性疾病状态中的快速血管生成治疗提供新靶点。
The rapid induction and orchestration of new blood vessels are critical for tissue repair in response to injury, such as myocardial infarction, and for physiological angiogenic responses, such as embryonic development and exercise. We aimed to identify and characterize microRNAs (miR) that regulate pathological and physiological angiogenesis. We show that miR-26a regulates pathological and physiological angiogenesis by targeting endothelial cell (EC) bone morphogenic protein/SMAD1 signaling in vitro and in vivo. MiR-26a expression is increased in a model of acute myocardial infarction 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 bone morphogenic protein/SMAD1 signaling pathway in ECs by binding to the SMAD1 3′-untranslated region, 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 bone morphogenic protein-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, locked nucleic acid-anti–miR-26a, increased SMAD1 expression and rapidly induced robust angiogenesis within 2 days, an effect associated with reduced myocardial infarct size and improved heart function. These findings establish miR-26a as a regulator of bone morphogenic protein/SMAD1-mediated EC angiogenic responses, and that manipulating miR-26a expression could provide a new target for rapid angiogenic therapy in ischemic disease states.