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Impairment in postischemic neovascularization in mice lacking the CXC chemokine receptor 3
Ludovic Waeckel1, Ziad Mallat, Stéphane Potteaux
1U541-INSERM, Hôpital Lariboisière, IFR Circulation-Lariboisière, Université Paris 7-Denis Diderot, Paris, France.
Insights
The CXC chemokine receptor 3 (CXCR3) is crucial for recruiting inflammatory cells and promoting blood vessel growth in ischemic tissues. Its absence significantly impairs neovascularization, highlighting its therapeutic potential.
Area of Science:
- Vascular biology
- Immunology
- Regenerative medicine
Background:
- Inflammatory cell infiltration is key to post-ischemic neovascularization.
- Mechanisms of leukocyte attraction to neovascularization sites are not fully understood.
Purpose of the Study:
- To investigate the role of CXC chemokine receptor 3 (CXCR3) in leukocyte recruitment and neovascularization in an ischemic limb model.
Main Methods:
- Induction of hindlimb ischemia in wild-type and CXCR3-deficient mice.
- Assessment of neovascularization using angiography, blood flow measurements, and capillary density.
- Quantification of immune cell infiltration (T cells, monocytes/macrophages) and VEGF levels.
- Bone marrow chimeric studies using wild-type and CXCR3-deficient cells.
Main Results:
- CXCR3-deficient mice showed significantly reduced neovascularization and blood flow recovery compared to controls.
- Leukocyte infiltration, particularly T cells and macrophages, was markedly lower in CXCR3-deficient mice.
- Vascular endothelial growth factor (VEGF) protein levels were significantly reduced in the ischemic limbs of CXCR3-deficient mice.
- Restoration of neovascularization in CXCR3-deficient mice was achieved by wild-type bone marrow-derived mononuclear cells.
Conclusions:
- CXC chemokine receptor 3 (CXCR3) plays a critical role in mediating leukocyte infiltration and promoting neovascularization in ischemic limbs.
- CXCR3 signaling is essential for effective blood vessel repair and growth following ischemia.
- Targeting CXCR3 may offer a novel therapeutic strategy for enhancing neovascularization in ischemic diseases.
Abstract:
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.
