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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1014.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Repopulation of Apolipoprotein E Knockout Mice With CCR2-Deficient Bone Marrow Progenitor Cells Does Not Inhibit Ongoing Atherosclerotic Lesion Development

Jian Guo; Vivian de Waard; Miranda Van Eck; Reeni B. Hildebrand; Eva J.A. van Wanrooij; Johan Kuiper; Nobuyo Maeda; G. Martin Benson; Pieter H.E. Groot; Theo J.C. Van Berkel

From Division of Biopharmaceutics (J.G., V.d.W., M.V.E., R.B.H., E.J.A.W., J.K., T.J.C.V.B.), Gorlaeus Laboratories, Leiden University, Leiden, the Netherlands; Department of Pathology and Laboratory Medicine (N.M.), University of North Carolina Medical School, Chapel Hill, NC; Atherosclerosis Department (M.B., P.H.E.G.), GlaxoSmithKline Pharmaceuticals, Stevenage, UK.

Correspondence to Theo J. C. Van Berkel, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research (LACDR), Gorlaeus Laboratories, Leiden University, Einsteinweg 55, PO Box 9502, 2300 RA Leiden, the Netherlands. E-mail t.berkel{at}chem.leidenuniv.nl

Objective— Using bone marrow transplantation, we have previously demonstrated the critical role that hematopoietic CCR2 plays in early atherogenesis. Reconstitution of irradiated apolipoprotein (apo) E3–Leiden mice with CCR2-deficient bone marrow progenitor cells resulted in 86% reduction on overall atherosclerotic lesion development. However, no data on CCR2 in the cause of established atherosclerosis have been reported so far.

Methods and Results— To study the role of CCR2 in established atherosclerotic lesions, bone marrow progenitor cells harvested from apoE^–/– and apoE^–/–/CCR2^–/– mice were transplanted into lethally irradiated 16-week-old apoE^–/– mice with established atherosclerotic lesions. No significant differences were found in serum total cholesterol and triglycerides levels at different time points after transplantation. At age 16 weeks, lesion size in control apoE^–/– mice was 3.28±1.06x10⁵ µm². At 9 weeks after transplantation, apoE^–/– apoE^–/– and apoE^–/–/CCR2^–/– apoE^–/– mice had developed significantly larger atherosclerotic lesions (4.49±0.92x10⁵ µm², P<0.02 and 4.15±0.62x10⁵ µm², P<0.04 compared with controls, respectively). However, no significant effect of disruption of hematopoietic CCR2 was observed on the progression of lesions. Furthermore, the macrophage positive area (78±4% versus 72±9%) and collagen content (11±6% versus 15±3%) of the lesions were similar as well.

Conclusion— In contrast to the critical role of CCR2 in the initiation of atherogenesis, bone marrow progenitor cell-derived CCR2 does not influence the progression of established atherosclerotic lesions, pointing to additional mechanisms for recruitment of monocytes at later stages of lesion development.

Repopulation of apoE knockout mice with CCR2-deficient bone marrow progenitor cells demonstrates that hematopoietic CCR2 does not have a great effect on the progression of established atherosclerotic lesions and lesion composition, ie, macrophage and collagen content, and certainly does not result in lesion regression.

Key Words: bone marrow transplantation • CCR2 • regression of atherosclerosis

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