Impairment in postischemic neovascularization in mice lacking the CXC chemokine receptor 3.
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.
Waeckel
Ludovic
L
U541-INSERM, Hôpital Lariboisière, IFR Circulation-Lariboisière, Université Paris 7-Denis Diderot, Paris, France.
Mallat
Ziad
Z
Potteaux
Stéphane
S
Combadière
Christophe
C
Clergue
Michel
M
Duriez
Micheline
M
Bao
Lu
L
Gerard
Craig
C
Rollins
Barrett J
BJ
Tedgui
Alain
A
Levy
Bernard I
BI
Silvestre
Jean-Sébastien
JS
D000818:Animals; D001160:Arterioles / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002196:Capillaries / Q000378:metabolism; D018932:Chemokine CCL2 / Q000172:deficiency / Q000502:physiology; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D005263:Femoral Artery; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000503:physiopathology* / Q000628:therapy; D017078:Laser-Doppler Flowmetry; D008026:Ligation; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D042461:Vascular Endothelial Growth Factor A