MicroRNA-26a Regulates Pathological and Physiological Angiogenesis by Targeting BMP/SMAD1 Signaling

Abstract

Rationale 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. Objective We aimed to identify and characterize microRNAs (miR) that regulate pathological and physiological angiogenesis. Methods and Results 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. Conclusions 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.

The regulatory role of microRNAs in angiogenesis‐related diseases

“…MiR‐26a can be down‐regulated by pro‐angiogenic stimuli such as VEGF or TNF, which can inhibit angiogenesis via targeting the SMAD1–Id1–p21 WAF/CIP1 /p27 signalling axis in ECs 116. Importantly, a study showed that the inhibition of miR‐26a can rapidly enhance angiogenesis and decrease AMI size with improved heart function in a mouse model of AMI, while overexpression miR‐26a leads to the opposite results 117. Mechanically, miR‐26a represses VEGF signalling via directly targeting NgBR, and therefore inhibit angiogenesis by performing proliferation, migration and tube formation in HUVECs 118.…”

“…Moreover, plasma miR‐26a is up‐regulated in a model of AMI in mice and in human beings with ACS 117. Interestingly, recent discoveries showed that circulating miR‐214 was up‐regulated in the early phase after AMI but then gradually decreased to near normal levels 163.…”

“…Mechanically, miR‐1 is enriched in cardiomyocytes and modulates myogenesis, cardiac development and hypertrophy, and miR‐208 is a cardiac‐specific miRNA expressed by introns of myosin heavy chains and involved in stress‐dependent cardiac growth and gene expression 165. Furthermore, the up‐regulated miR‐26a in AMI can inhibit angiogenesis, and thereby aggravates MI 117. However, further studies are necessary and important for exploring the role and mechanism of other specific miRNAs in the regulation of CVD pathogenesis.…”

Scaffold‐Based microRNA Therapies in Regenerative Medicine and Cancer

“…Importantly, these two-stage, cell-free, miR-26a loaded scaffolds demonstrated significantly enhanced bone regeneration in critical-sized calvarial bone defects in both healthy and osteoporotic mice after only 8 weeks. miR-26a has previously been shown to regulate suppression of connective tissue growth factor, [147] angiogenesisthrough bone morphogenetic protein 2 (BMP2)/drosophila mothers against decapentaplegic protein (SMAD) signaling -in endothelial cells, [148] and atherosclerosis via a EphA2/p38 MAPK/vascular endothelial growth factor (VEGF) pathway. [149] Work by Luzi et al [150] has however pointed at a complex role for the miR-26a::SMAD1 match in human ASCs osteogenesis.…”

Renal Vein Levels of MicroRNA-26a Are Lower in the Poststenotic Kidney

“…6 miR-26a is abundant in cardiac and other tissues and promotes vascular smooth muscle cell proliferation but inhibits cellular differentiation, apoptosis, 7 and angiogenesis. 8 In mice, lack of mature podocyte miRs induces marked proteinuria and glomerular and tubular injury. Furthermore, glomerular miR-26a expression implies a possible role in preservation of glomerular filtration barrier function.…”