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(Circulation. 2005;112:2501-2509.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Delayed Arteriogenesis in Hypercholesterolemic Mice

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

From the Angiogenesis Research Center, Section of Cardiology (D.T., K.L.M., Z.W.Z., K.S., A.H., M.S.), Departments of Medicine (D.T., K.L.M., Z.W.Z., K.S., A.H., M.S.), Pharmacology & Toxicology (M.S.), and Radiology (J.F.D.), Dartmouth Medical School, Lebanon, NH, and Eli Lilly & Co, Indianapolis, Ind (W.L., J.S.).

Correspondence to Michael Simons, MD, Section of Cardiology, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756. E-mail michael.simons{at}dartmouth.edu

Received February 14, 2005; revision received July 25, 2005; accepted July 27, 2005.

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-1, 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.

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