Delayed arteriogenesis in hypercholesterolemic mice

Daniela Tirziu, Karen L. Moodie, Zhen W. Zhuang, Katie Singer, Armin Helisch, Jeff F. Dunn, Weiming Li, Jaipal Singh, Michael Simons

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Background - Hypercholesterolemia has been reported to inhibit ischemia-induced angiogenesis. To address its effects on arteriogenesis, we investigated arterial growth in hypercholesterolemic low-density lipoprotein receptor-/-/ApoB-48-/- (HCE) mice. Methods and Results - The extent and the time course of arteriogenesis after femoral artery ligation was evaluated in HCE and strain-matched control mice. Distal limb perfusion was measured by laser Doppler imaging, whereas MRI was used to visualize arterial flow and micro-computed tomography to assess vascular growth. After femoral artery ligation, serial laser Doppler imaging demonstrated significantly delayed restoration of perfusion in untreated HCE compared with control mice (day 3, 0.09 versus 0.19, P<0.05). Treatment with Ad-PR39 in control mice led to a significant restoration of arterial blood flow and tissue perfusion at day 3, whereas in HCE mice, hindlimb perfusion began increasing only by day 7. Micro-CT analysis confirmed increased growth of smaller arterioles (16 to 63 μm in diameter) in the Ad-PR39-treated control compared with HCE mice. The delay in arteriogenesis in HCE mice correlated with delayed tissue appearance of F4/80- cells. Analysis of gene expression after Ad-PR39 treatment demonstrated that HCE mice had significantly reduced expression of FGF receptor 1, hypoxia-inducible factor-1α, vascular cell adhesion molecule-1, macrophage scavenger receptor-1, and cyclophilin A compared with controls 3 days after arterial ligation that equalized by day 7, mimicking relative changes in arteriogenesis and tissue perfusion. Conclusions - Hypercholesterolemia results in delayed native arteriogenesis because of reduced early monocyte/macrophage influx and delayed and impaired arterial growth response to growth factor therapy.

Original languageEnglish (US)
Pages (from-to)2501-2509
Number of pages9
JournalCirculation
Volume112
Issue number16
DOIs
StatePublished - Oct 18 2005

Keywords

  • Arteries
  • Arteriogenesis
  • Atherosclerosis
  • Gene therapy
  • Genes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Tirziu, D., Moodie, K. L., Zhuang, Z. W., Singer, K., Helisch, A., Dunn, J. F., Li, W., Singh, J., & Simons, M. (2005). Delayed arteriogenesis in hypercholesterolemic mice. Circulation, 112(16), 2501-2509. https://doi.org/10.1161/CIRCULATIONAHA.105.542829