MicroRNA-26a regulates pathological and physiological angiogenesis by targeting BMP/SMAD1 signaling

Basak Icli, A. K.M. Wara, Javid Moslehi, Xinghui Sun, Eva Plovie, Meghan Cahill, Julio F. Marchini, Andrew Schissler, Robert F. Padera, Jianru Shi, Hui Wen Cheng, Srilatha Raghuram, Zoltan Arany, Ronglih Liao, Kevin Croce, Calum Macrae, Mark W. Feinberg

Research output: Contribution to journalArticlepeer-review

183 Scopus citations


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 p21 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.

Original languageEnglish (US)
Pages (from-to)1231-1241
Number of pages11
JournalCirculation Research
Issue number11
StatePublished - Nov 8 2013
Externally publishedYes


  • angiogenesis effect
  • endothelial cells
  • microRNAs
  • myocardial infarction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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