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Region-specific patterns of vascular remodelling occur early in atherosclerosis and without loss of smooth muscle cell markers

  • Shivalika Handa
    Affiliations
    Department of Laboratory Medicine & Pathobiology, University of Toronto, Canada

    Heart & Stroke Richard Lewar Centre for Excellence in Cardiovascular Research, University of Toronto, Canada
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  • Al Muktafi Sadi
    Affiliations
    Division of Cell & Molecular Biology, Toronto General Hospital Research Institute, Canada
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  • Myron I. Cybulsky
    Affiliations
    Department of Laboratory Medicine & Pathobiology, University of Toronto, Canada

    Division of Cell & Molecular Biology, Toronto General Hospital Research Institute, Canada

    Heart & Stroke Richard Lewar Centre for Excellence in Cardiovascular Research, University of Toronto, Canada
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  • Author Footnotes
    1 These authors have contributed equally.
    Duncan J. Stewart
    Footnotes
    1 These authors have contributed equally.
    Affiliations
    Department of Medicine, University of Toronto, Canada

    Department of Laboratory Medicine & Pathobiology, University of Toronto, Canada

    Terrence Donelly Research Centre, St. Michael's Hospital, Toronto, Canada

    Heart & Stroke Richard Lewar Centre for Excellence in Cardiovascular Research, University of Toronto, Canada
    Search for articles by this author
  • Author Footnotes
    1 These authors have contributed equally.
    Mansoor Husain
    Correspondence
    Corresponding author at: University Health Network, 200 Elizabeth Street, MaRS 3-909, Toronto, Ont. M5G 2C4, Canada. Tel.: +1 416 340 3188; fax: +1 416 340 4021.
    Footnotes
    1 These authors have contributed equally.
    Affiliations
    Department of Medicine, University of Toronto, Canada

    Department of Laboratory Medicine & Pathobiology, University of Toronto, Canada

    Division of Cell & Molecular Biology, Toronto General Hospital Research Institute, Canada

    Heart & Stroke Richard Lewar Centre for Excellence in Cardiovascular Research, University of Toronto, Canada
    Search for articles by this author
  • Author Footnotes
    1 These authors have contributed equally.

      Abstract

      Background

      Vascular remodelling is characterized by increased smooth muscle cell (SMC) proliferation and migration. Coincident with these events, SMC markers of differentiation are known to down-regulate in advanced stages of atherosclerosis, a process known as phenotypic modulation. However, it is not known when this first begins. Here we sought to determine if regions of the mouse aorta with varying susceptibilities for atherosclerosis display differential vascular remodelling and SMC gene expression at the earliest stages of disease.

      Methods and results

      LDLrKO mice were fed normal or high cholesterol diet for 0–98 days. In the latter, ORO and H&E staining of arch, thoracic and abdominal aortic sections revealed infrequent occurrences of lipid deposition at d28, but significant region-specific vascular remodelling. Immunostaining for PCNA revealed increased cellular proliferation in the intima and inner media at d28 in all three regions. qRT-PCR of SMC revealed increased expression of SM22α and SM-MHC in the arch by d28, which subsequently decreased by d98. By contrast, eNOS gene expression was consistently decreased in the arch over these times. A temporal increase in macrophage-specific CD68 expression was observed in the arch but not thoracic or abdominal regions.

      Conclusion

      Remodelling of the vascular myocyte compartment due to cellular proliferation is an early event in atherosclerosis and is associated with increases in SMC-specific gene expression. These events precede subsequent lesion formation and SMC phenotypic modulation.

      Keywords

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