title: MicroRNA-26a regulates pathological and physiological angiogenesis by targeting BMP/SMAD1 signaling.
abstract: BACKGROUND
  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.
  
  
  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(WAF/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.
authors.affiliation: From the Cardiovascular Division, Departments of Medicine (B.I., A.K.M.W., J.M., X.S., E.P., M.C., J.F.M., A.S., J.S., H.-W.C., R.L., K.C., C.M., M.W.F.) and Pathology (R.F.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (S.R., Z.A.).
authors.forename: Basak
authors.initials: B
authors.lastname: Icli
authors.forename: A K M
authors.initials: AK
authors.lastname: Wara
authors.forename: Javid
authors.initials: J
authors.lastname: Moslehi
authors.forename: Xinghui
authors.initials: X
authors.lastname: Sun
authors.forename: Eva
authors.initials: E
authors.lastname: Plovie
authors.forename: Meghan
authors.initials: M
authors.lastname: Cahill
authors.forename: Julio F
authors.initials: JF
authors.lastname: Marchini
authors.forename: Andrew
authors.initials: A
authors.lastname: Schissler
authors.forename: Robert F
authors.initials: RF
authors.lastname: Padera
authors.forename: Jianru
authors.initials: J
authors.lastname: Shi
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Cheng
authors.forename: Srilatha
authors.initials: S
authors.lastname: Raghuram
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Arany
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.forename: Kevin
authors.initials: K
authors.lastname: Croce
authors.forename: Calum
authors.initials: C
authors.lastname: MacRae
authors.forename: Mark W
authors.initials: MW
authors.lastname: Feinberg
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D015415:Biomarkers / Q000097:blood; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D047108:Embryonic Development / Q000502:physiology; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000097:blood / Q000502:physiology*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051898:Smad1 Protein / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000502:physiology; D015027:Zebrafish
chemical_list: D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D035683:MicroRNAs; D051898:Smad1 Protein; C528163:MIRN26 microRNA, human; C543693:Mirn26 microRNA, mouse; C569904:Mirn26 microRNA, zebrafish
keywords: angiogenesis effect; endothelial cells; microRNAs; myocardial infarction
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