title: MicroRNA-100 regulates neovascularization by suppression of mammalian target of rapamycin in endothelial and vascular smooth muscle cells.
abstract: BACKGROUND
  The adaptive growth of blood vessels is an important protective mechanism in cardiovascular disease. However, the underlying regulatory mechanisms of this process are only partly understood. Recently, small endogenous RNAs (microRNAs [miRNAs]) were found to play an important role in embryonic and postnatal vascular development. Here, we used miRNA transcriptome analysis after induction of hind-limb ischemia in mice to screen for miRNAs involved in adaptive blood vessel growth following arterial occlusion.
  
  
  RESULTS
  Using miRNA arrays, we explored the miRNA expression profile during adaptive neovascularization. We describe specific changes in miRNA expression patterns and show that miRNA-100 is significantly downregulated after induction of hind-limb ischemia in mice. Our data demonstrate that miR-100 modulates proliferation, tube formation, and sprouting activity of endothelial cells and migration of vascular smooth muscle cells and functions as an endogenous repressor of the serine/threonine protein kinase mammalian target of rapamycin (mTOR). Whereas miR-100 inhibition increased mTOR levels in endothelial cells, overexpression of miR-100 reduced mTOR expression and consequently attenuated cellular proliferation. Supporting this notion, overexpression of an mTOR construct lacking the miRNA binding site rescued the inhibitory effect of miR-100 on cell proliferation. Accordingly, miR-100 inhibition by specific antagomirs in vivo stimulated angiogenesis and resulted in functional improvement of perfusion after femoral artery occlusion in mice. In contrast, treatment with the mTOR inhibitor rapamycin had the opposite effect.
  
  
  CONCLUSIONS
  Our data demonstrate that miR-100 has an antiangiogenic function and represses mTOR signaling in endothelial and vascular smooth muscle cells. Inhibition of miR-100 could be a novel approach for the modulation of blood vessel growth and other mTOR-dependent processes.
authors.affiliation: Department of Internal Medicine III-Cardiology and Angiology, University Hospital Freiburg, Breisacher Strasse 33, 79106 Freiburg, Germany. sebastian.grundmann@uniklinik-freiburg.de
authors.forename: Sebastian
authors.initials: S
authors.lastname: Grundmann
authors.forename: Felix P
authors.initials: FP
authors.lastname: Hans
authors.forename: Sheena
authors.initials: S
authors.lastname: Kinniry
authors.forename: Jennifer
authors.initials: J
authors.lastname: Heinke
authors.forename: Thomas
authors.initials: T
authors.lastname: Helbing
authors.forename: Franziska
authors.initials: F
authors.lastname: Bluhm
authors.forename: Joost P G
authors.initials: JP
authors.lastname: Sluijter
authors.forename: Imo
authors.initials: I
authors.lastname: Hoefer
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Martin
authors.initials: M
authors.lastname: Moser
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D057809:HEK293 Cells; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D035683:MicroRNAs; C558180:Mirn100 microRNA, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases