title: MicroRNA miR145 regulates TGFBR2 expression and matrix synthesis in vascular smooth muscle cells.
abstract: BACKGROUND
  MicroRNA miR145 has been implicated in vascular smooth muscle cell differentiation, but its mechanisms of action and downstream targets have not been fully defined.
  
  
  OBJECTIVE
  Here, we sought to explore and define the mechanisms of miR145 function in smooth muscle cells.
  
  
  RESULTS
  Using a combination of cell culture assays and in vivo mouse models to modulate miR145, we characterized its downstream actions on smooth muscle phenotypes. Our results show that the miR-143/145 gene cluster is induced in smooth muscle cells by coculture with endothelial cells. Endothelial cell-induced expression of miR-143/145 is augmented by Notch signaling and accordingly expression is reduced in Notch receptor-deficient cells. Screens to identify miR145-regulated genes revealed that the transforming growth factor (TGF)-β pathway has a significantly high number of putative target genes, and we show that TGFβ receptor II is a direct target of miR145. Extracellular matrix genes that are regulated by TGFβ receptor II were attenuated by miR145 overexpression, and miR145 mutant mice exhibit an increase in extracellular matrix synthesis. Furthermore, activation of TGFβ signaling via angiotensin II infusion revealed a pronounced fibrotic response in the absence of miR145.
  
  
  CONCLUSIONS
  These data demonstrate a specific role for miR145 in the regulation of matrix gene expression in smooth muscle cells and suggest that miR145 acts to suppress TGFβ-dependent extracellular matrix accumulation and fibrosis, while promoting TGFβ-induced smooth muscle cell differentiation. Our findings offer evidence to explain how TGFβ signaling exhibits distinct downstream actions via its regulation by a specific microRNA.
authors.affiliation: From the Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.affiliation: From the Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus.
authors.forename: Sara N
authors.initials: SN
authors.lastname: Koenig
authors.affiliation: From the Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Trask
authors.affiliation: From the Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus.
authors.forename: Cho-Hao
authors.initials: CH
authors.lastname: Lin
authors.affiliation: From the Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus.
authors.forename: Chetan P
authors.initials: CP
authors.lastname: Hans
authors.affiliation: From the Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus.
authors.forename: Vidu
authors.initials: V
authors.lastname: Garg
authors.affiliation: From the Center for Cardiovascular and Pulmonary Research and Heart Center, Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus. brenda.lilly@nationwidechildrens.org.
authors.forename: Brenda
authors.initials: B
authors.lastname: Lilly
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis*
chemical_list: C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: extracellular matrix; microRNAs; myocytes, smooth muscle; transforming growth factors