title: Uremia modulates the phenotype of aortic smooth muscle cells.
abstract: Chronic kidney disease leads to uremia and markedly accelerates atherosclerosis. Phenotypic modulation of smooth muscle cells (SMCs) in the arterial media plays a key role in accelerating atherogenesis. The aim of this study was to investigate whether uremia per se modulates the phenotype of aortic SMCs in vivo.
  
  
  
  Moderate uremia was induced by 5/6 nephrectomy in apolipoprotein E knockout (ApoE-/-) and wildtype C57Bl/6 mice. Plasma analysis, gene expression, histology, and myography were used to determine uremia-mediated changes in the arterial wall.
  
  
  
  Induction of moderate uremia in ApoE-/-mice increased atherosclerosis in the aortic arch en face 1.6 fold (p = 0.04) and induced systemic inflammation. Based on histological analyses of aortic root sections, uremia increased the medial area, while there was no difference in the content of elastic fibers or collagen in the aortic media. In the aortic arch, mRNA and miRNA expression patterns were consistent with a uremia-mediated phenotypic modulation of SMCs; e.g. downregulation of myocardin, α-smooth muscle actin, and transgelin; and upregulation of miR146a. Notably, these expression patterns were observed after acute (2 weeks) and chronic (19 and 30 weeks) uremia, both under normo- and hypercholesterolemic settings. Functionally, aortic constriction was decreased in uremic as compared to non-uremic aorta segments, as measured by myography.
  
  
  
  Uremia modulates the phenotype of aortic SMCs as determined by mRNA/miRNA expression, an increased medial area, and decreased aortic contractility. We propose that this phenotypic modulation of SMCs precedes the acceleration of atherosclerosis observed in uremic mice.
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
authors.forename: Marie
authors.initials: M
authors.lastname: Madsen
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Aarup
authors.affiliation: Department of Experimental Medical Science, University of Lund, Sölveg 19, Lund, Sweden.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Albinsson
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
authors.forename: Karsten
authors.initials: K
authors.lastname: Hartvigsen
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Sørensen
authors.affiliation: Department of Experimental Medical Science, University of Lund, Sölveg 19, Lund, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Turczynska
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark.
authors.forename: Lars B
authors.initials: LB
authors.lastname: Nielsen
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark. Electronic address: tanjax@sund.ku.dk.
authors.forename: Tanja Xenia
authors.initials: TX
authors.lastname: Pedersen
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001018:Aortic Diseases / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D007249:Inflammation / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014511:Uremia / Q000097:blood / Q000150:complications*; D014661:Vasoconstriction
chemical_list: D001057:Apolipoproteins E; D035683:MicroRNAs; D012333:RNA, Messenger
keywords: Phenotypic modulation; Smooth muscle cells; Uremia