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Uremia modulates the phenotype of aortic smooth muscle cells

Madsen, Marie; Aarup, Annemarie; Albinsson, Sebastian LU ; Hartvigsen, Karsten; Sørensen, Charlotte M.; Turczynska, Karolina LU ; Nielsen, Lars B. LU and Pedersen, Tanja Xenia (2017) In Atherosclerosis 257. p.64-70
Abstract

Background and aims 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. Methods 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. Results Induction of moderate uremia in ApoE-/- mice increased atherosclerosis in the aortic arch en face 1.6 fold (p = 0.04) and induced... (More)

Background and aims 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. Methods 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. Results 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. Conclusions 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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Phenotypic modulation, Smooth muscle cells, Uremia
in
Atherosclerosis
volume
257
pages
64 - 70
publisher
Elsevier
external identifiers
  • scopus:85009343994
  • wos:000397405600009
ISSN
0021-9150
DOI
10.1016/j.atherosclerosis.2016.12.022
language
English
LU publication?
yes
id
725c0b88-db68-4f54-85b7-d597d12dfa8f
date added to LUP
2017-02-03 14:44:56
date last changed
2018-10-28 04:40:23
@article{725c0b88-db68-4f54-85b7-d597d12dfa8f,
  abstract     = {<p>Background and aims 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. Methods Moderate uremia was induced by 5/6 nephrectomy in apolipoprotein E knockout (ApoE<sup>-/-</sup>) and wildtype C57Bl/6 mice. Plasma analysis, gene expression, histology, and myography were used to determine uremia-mediated changes in the arterial wall. Results Induction of moderate uremia in ApoE<sup>-/-</sup> 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. Conclusions 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.</p>},
  author       = {Madsen, Marie and Aarup, Annemarie and Albinsson, Sebastian and Hartvigsen, Karsten and Sørensen, Charlotte M. and Turczynska, Karolina and Nielsen, Lars B. and Pedersen, Tanja Xenia},
  issn         = {0021-9150},
  keyword      = {Phenotypic modulation,Smooth muscle cells,Uremia},
  language     = {eng},
  month        = {02},
  pages        = {64--70},
  publisher    = {Elsevier},
  series       = {Atherosclerosis},
  title        = {Uremia modulates the phenotype of aortic smooth muscle cells},
  url          = {http://dx.doi.org/10.1016/j.atherosclerosis.2016.12.022},
  volume       = {257},
  year         = {2017},
}