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Flow patterns regulate hyperglycemia-induced subendothelial matrix remodeling during early atherogenesis

  • Jonette Green
    Affiliations
    Department of Pathology, LSU Health Sciences Center – Shreveport, Biomedical Research Institute, Rm. 6-21, 1501 Kings Hwy, Shreveport, LA 71130, USA
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  • Arif Yurdagul Jr.
    Affiliations
    Department of Cell Biology and Anatomy, LSU Health Sciences Center – Shreveport, Shreveportt, LA 71130, USA
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  • Marshall C. McInnis
    Affiliations
    Department of Pathology, LSU Health Sciences Center – Shreveport, Biomedical Research Institute, Rm. 6-21, 1501 Kings Hwy, Shreveport, LA 71130, USA
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  • Patrick Albert
    Affiliations
    Department of Pathology, LSU Health Sciences Center – Shreveport, Biomedical Research Institute, Rm. 6-21, 1501 Kings Hwy, Shreveport, LA 71130, USA
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  • A. Wayne Orr
    Correspondence
    Corresponding author. Department of Pathology, LSU Health Sciences Center – Shreveport, Biomedical Research Institute, Rm. 6-21, 1501 Kings Hwy, Shreveport, LA 71130, USA. Tel.: +1 (318) 675 5462; fax +1 (318) 675 8144.
    Affiliations
    Department of Pathology, LSU Health Sciences Center – Shreveport, Biomedical Research Institute, Rm. 6-21, 1501 Kings Hwy, Shreveport, LA 71130, USA

    Department of Cell Biology and Anatomy, LSU Health Sciences Center – Shreveport, Shreveportt, LA 71130, USA
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      Highlights

      • Diabetes promotes transitional matrix deposition in atherosclerosis-prone arteries.
      • Fibronectin deposition is limited to regions of disturbed blood flow.
      • Diabetes does not induced matrix remodeling in regions exposed to laminar flow.
      • Laminar flow blunts hyperglycemia-induced matrix remodeling in endothelial cells.

      Abstract

      Objective

      Altered subendothelial matrix composition regulates endothelial dysfunction and early atherosclerotic plaque formation. Hyperglycemia promotes endothelial matrix remodeling associated with multiple microvascular complications of diabetes, but a role for altered matrix composition in diabetic atherogenesis has not been described. Therefore, we sought to characterize the alterations in matrix composition during diabetic atherogenesis using both in vitro and in vivo model systems.

      Methods and results

      Streptozotocin-induced diabetes in atherosclerosis-prone ApoE knockout mice promoted transitional matrix expression (fibronectin, thrombospondin-1) and deposition in intima of the aortic arch as determined by qRT-PCR array and immunohistochemistry. Early plaque formation occurs at discrete vascular sites exposed to disturbed blood flow patterns, whereas regions exposed to laminar flow are protected. Consistent with this pattern, hyperglycemia-induced transitional matrix deposition was restricted to regions of disturbed blood flow. Laminar flow significantly blunted high glucose-induced fibronectin expression (mRNA and protein) and fibronectin fibrillogenesis in endothelial cell culture models, whereas high glucose-induced fibronectin deposition was similar between disturbed flow and static conditions.

      Conclusions

      Taken together, these data demonstrate that flow patterns and hyperglycemia coordinately regulate subendothelial fibronectin deposition during early atherogenesis.

      Keywords

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