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Published online before print May 9, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0206087

Received for publication February 7, 2006.
Revised March 20, 2006.
Accepted for publication March 28, 2006.

Article

Arteriogenesis depends on circulating monocytes and macrophage accumulation and is severely depressed in op/op mice

Caroline E. Bergmann ^*, Imo E. Hoefer ^*@, Benjamin Meder ^*, Holger Roth , Niels van Royen , Sabine M. Breit ^¶, Marco M. Jost ^*, Seyedhossein Aharinejad ^||, Susanne Hartmann ^*, and Ivo R. Buschmann ^***

*Research Group for Experimental and Clinical Arteriogenesis, Freiburg, Germany; Department of Experimental Cardiology, UMC Utrecht, Netherlands; Phoenix X-ray Systems + Services GmbH, Stuttgart, Germany; Department of Cardiology, AMC Amsterdam, Netherlands; ^¶Institute of Anatomy, Department of Pathobiology, University of Veterinary Medicine Vienna, Austria; ^||Center of Anatomy and Cellbiology, Medical University of Vienna, Austria; and **Charité, Department of Cardiology, Center for Cardiovascular Research CCR, Berlin, Germany

^@ To whom correspondence should be addressed. E-mail: i.hoefer{at}umcutrecht.nl.

	Abstract

It has been suggested that monocytes/macrophages represent the pivotal cell type during early adaptive growth of pre-existent arterial anastomoses toward functional collateral arteries (arteriogenesis) upon arterial occlusion. This hypothesis was supported by previous studies providing evidence that elevation of the peripheral monocyte count, increased monocyte survival (e.g., granulocyte macrophage-colony stimulating factor), as well as enhanced attraction or adhesion (e.g., monocyte chemoattractant protein 1; intercellular adhesion molecule 1) of the latter cells correlates directly with the arteriogenic response to restore tissue perfusion. However, the experimental proof of the essential role of monocytes/macrophages remains to be given. We therefore hypothesized that arteriogenesis is reduced in a genuine, nonpharmocologically induced monocyte/macrophage-deficient model of femoral artery occlusion in osteopetrotic (op/op) mice. Total leukocyte count did not differ between op/op mice and control (B6C3Fe a/a-Csf1^+/+) mice. op/op mice show a significant monocytopenia (0.67%±0.38% vs. 1.53%±0.32%), granulocytosis (33.66%±6.67% vs. 22.83±7.47%), and a concomitant, relative lymphopenia (65.67%±6.58% vs. 75.65%±7.31%). Microsphere-based perfusion measurement 7 days after femoral artery occlusion demonstrated a significantly reduced perfusion restoration upon femoral artery occlusion in op/op mice as compared with controls (28.19%±0.91% vs. 47.88%±2.49%). The application of a novel method of high resolution (microfocus X-ray system) angiography revealed a reduction of proliferation and diameter of collateral arteries. Quantitative immunohistology showed significantly lower numbers of macrophages in the surrounding tissue of proliferating arteries. This study provides additional evidence for the preeminent role of monocytes/macrophages during arteriogenesis in a genuine model of monocyte deficiency, i.e., without pharmacological intervention.

Key Words: collateral artery growth • peripheral vascular disease

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