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(Circulation Research. 2005;96:576.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Impairment in Postischemic Neovascularization in Mice Lacking the CXC Chemokine Receptor 3

Ludovic Waeckel, Ziad Mallat, Stéphane Potteaux, Christophe Combadière, Michel Clergue, Micheline Duriez, Lu Bao, Craig Gerard, Barrett J. Rollins, Alain Tedgui, Bernard I. Levy, Jean-Sébastien Silvestre

From the INSERM U541 Hôpital Lariboisière (L.W., Z.M., S.P., M.C., M.D., A.T., B.I.L., J.-S.S.), IFR Circulation-Lariboisière, Université Paris 7-Denis Diderot, Paris, France; INSERM U543 (C.C.), Laboratoire d’immunologie cellulaire et tissulaire, Hôpital Pitié-Salpétrière, Paris, France; the Ina Sue Perlmutter Laboratory (L.B., C.G.), Children‘s Hospital, Harvard Medical School, Boston, Mass; and the Department of Medical Oncology (B.J.R.), Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Jean-Sebastien Silvestre, U541-INSERM, Hôpital Lariboisière, 41 Bd de la Chapelle, 75475 Paris cedex 10, France. E-mail Jean-Sebastien.Silvestre{at}larib.inserm.fr

Inflammatory cell infiltration is a feature of postischemic neovascularization. However, mechanisms leading to leukocyte attraction to the site of neovascularization are still undefined. We hypothesized that the CXC chemokine receptor 3 (CXCR3) may contribute to leukocyte accumulation and subsequently to blood vessel growth in the ischemic area. Ischemia induced by femoral artery ligature improved the number of CXCR3-expressing cells and the level of its ligand, CXCL10. Angiographic score, blood flow recovery measurement, and capillary density analysis showed a significant decrease of ischemic/nonischemic leg ratio in CXCR3-deficient mice when compared with controls (P<0.05), at day 21 after ischemia. Interestingly, this impairment was as important as that observed in mice deficient for the well known CC-chemokine monocyte chemoattractant protein-1 (MCP-1). At day 7 of ischemic injury, the number of CD3-positive T cells and Mac-3–positive monocytes/macrophages was 38% and 45% lower, respectively, in the ischemic leg of CXCR3-deficient mice compared with the control group (P<0.05), suggesting an important role for CXCR3 in leukocyte recruitment into the ischemic area. VEGF protein content, a classical proangiogenic factor, was also markedly reduced (80% reduction) in ischemic leg of CXCR3-deficient mice (P<0.01). Injection of bone marrow–derived mononuclear cells (BM-MNCs) isolated from wild-type animals restored the neovascularization reaction in CXCR3-deficient mice whereas BM-MNCs from CXCR3-deficient mice was ineffective. In conclusion, CXCR3 plays a key role in neovascularization and provides novel information on the mechanisms leading to leukocyte infiltration in the vessel growth area.

Key Words: inflammation • angiogenesis • ischemia • chemokine receptor

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