Impairment in Postischemic Neovascularization in Mice Lacking the CXC Chemokine Receptor 3 (original) (raw)
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Role of CX3CR1 receptor in monocyte/macrophage driven neovascularization
PloS one, 2013
Monocyte/macrophages are implicated in initiation of angiogenesis, tissue/organ perfusion and atherosclerosis biology. We recently showed that chemokine receptor CX(3)CR1 is an essential regulator of monocyte/macrophage derived smooth muscle cell differentiation in the vessel wall after injury. Here we hypothesised the contribution of CX(3)CR1- CX(3)CL1 interaction to in vivo neovascularization and studied the functional consequences of genetic and pharmacologic targeting of CX(3)CR1 in formation, maturation and maintenance of microvascular integrity. Cells functionally deficient in CX(3)CR1 lacked matrix tunnelling and tubulation capacity in a 3D Matrigel assay. These morphogenic and cytokinetic responses were driven by CX(3)CL1-CX(3)CR1 interaction and totally abrogated by a Rho antagonist. To evaluate the role of CX(3)CR1 system in vivo, Matrigel plugs were implanted in competent CX(3)CR1(+/gfp) and functionally deficient CX(3)CR1(gfp/gfp) mice. Leaky microvessels (MV) were forme...
Journal of Experimental Medicine, 2010
Sustained changes in blood flow modulate the size of conduit arteries through structural alterations of the vessel wall that are dependent on the transient accumulation and activation of perivascular macrophages. The leukocytic infiltrate appears to be confined to the adventitia, is responsible for medial remodeling, and resolves once hemodynamic stresses have normalized without obvious intimal changes. We report that inward remodeling of the mouse common carotid artery after ligation of the ipsilateral external carotid artery is dependent on the chemokine receptor CXCR3. Wild-type myeloid cells restored flow-mediated vascular remodeling in CXCR3-deficient recipients, adventitia-infiltrating macrophages of Gr1low resident phenotype expressed CXCR3, the perivascular accumulation of macrophages was dependent on CXCR3 signaling, and the CXCR3 ligand IP-10 was sufficient to recruit monocytes to the adventitia. CXCR3 also contributed to selective features of macrophage activation require...
Circulation Research, 2004
Arteriogenesis has been associated with the presence of monocytes/macrophages within the collateral vessel wall. Induced macrophage migration in vivo is driven by the binding of monocyte chemoattractant protein-1 (MCP-1, or CCL2 in the new nomenclature) to the CCR2-chemokine receptor on macrophages. To determine whether the CCL2-CCR2 signaling pathway is involved in the accumulation of macrophages in growing collateral vessels, we used mice that are deficient in CCR2 in a model of experimental arterial occlusion and collateral vessel growth. In an in vitro CCL2-driven chemotaxis assay, mononuclear cells isolated from wild-type BALB/c mice exhibited CCL2 concentration-dependent migration, whereas this migration was abolished in cells from CCR2 Ϫ/Ϫ mice on a BALB/c genetic background. In vivo, blood flow recovery as measured by laser Doppler (LDI) and MRI (MRI) was impaired in CCR2 Ϫ/Ϫ mice on either the BALB/c or C57BL/6 genetic backgrounds. Three weeks after femoral artery ligation, LDI perfusion ratio of operated versus nonoperated distal hindlimb in BALB/c wild-type mice increased to 0.45Ϯ0.06 and in CCR2 Ϫ/Ϫ animals only to 0.21Ϯ0.03 (PϽ0.01). In C57BL/6 mice, ratio increased to 0.96Ϯ0.09 and 0.85Ϯ0.08 (PϽ0.05), respectively. MRI at 3 weeks (0.76Ϯ0.06 versus 0.62Ϯ0.01; PϽ0.05) and hemoglobin oxygen saturation measurements confirmed these findings. Active foot movement score significantly decreased and gastrocnemius muscle atrophy was significantly greater in CCR2 Ϫ/Ϫ mice. Morphometric analysis showed a lesser increase in collateral vessel diameters in CCR2 Ϫ/Ϫ mice. Importantly, the number of invaded monocytes/macrophages in the perivascular space of collateral arteries of CCR2 Ϫ/Ϫ animals was dramatically reduced in comparison to wild-type mice. In conclusion, our results demonstrate that the CCR2 signaling pathway is essential for efficient collateral artery growth. (Circ Res. 2004;94:671-677.)
Cardiovascular Research, 2010
Monocyte systemic levels are known to be a major determinant of ischaemic tissue revascularization, but the mechanisms mediating mobilization of different monocyte subsets-Ly6C hi and Ly6C lo -to the blood and their respective role in post-ischaemic neovascularization are not clearly understood. Here, we hypothesized that distinct chemokine/ chemokine receptor pathways, namely CCL2/CCR2, CX3CL1/CX3CR1, and CCL5/CCR5, differentially control monocyte subset systemic levels, and might thus impact post-ischaemic vessel growth.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2014
Objective— The Cxcl12/Cxcr4 chemokine ligand/receptor axis mediates the mobilization of smooth muscle cell progenitors, driving injury-induced neointimal hyperplasia. This study aimed to investigate the role of endothelial Cxcr4 in neointima formation. Approach and Results— β-Galactosidase staining using bone marrow x kinase ( Bmx ) -CreER T2 reporter mice and double immunofluorescence revealed an efficient and endothelial-specific deletion of Cxcr4 in Bmx-CreER T2+ compared with Bmx-CreER T2− Cxcr4-floxed apolipoprotein E–deficient ( Apoe −/− ) mice (referred to as Cxcr4 EC-KO ApoE −/− and Cxcr4 EC-WT ApoE −/− , respectively). Endothelial Cxcr4 deficiency significantly increased wire injury–induced neointima formation in carotid arteries from Cxcr4 EC-KO ApoE −/− mice. The lesions displayed a higher number of macrophages, whereas the smooth muscle cell and collagen content were reduced. This was associated with a significant reduction in reendothelialization and endothelial cell pr...
Deep Vein Thrombosis Resolution Is Modulated by Monocyte CXCR2-Mediated Activity in a Mouse Model
Arteriosclerosis, Thrombosis, and Vascular Biology, 2004
Objective-To determine the role of CXCR2, the receptor for cysteine-X-cysteine (CXC) chemokines, and its primary effector cell, the neutrophil (PMN), on deep venous thrombosis (DVT) resolution. Methods and Results-DVT in BALB/c, anti-CXCR2 antibody-treated, and BALB/c CXCR2 Ϫ/Ϫ mice were created by infrarenal inferior vena cava (IVC) ligation and the thrombus harvested at various time points over 21 days. The CXCR2 Ϫ/Ϫ mice had significantly larger thrombi at early time points (days 2 to 8), and significantly decreased intrathrombus PMNs, monocytes, and neovascularization as compared with controls. Thrombus KC/CXCL1 was significantly higher at 2 days in CXCR2 Ϫ/Ϫ thrombi as measured by enzyme-linked immunosorbent assay. Fibrin content was significantly higher, with less uPA gene expression at 4 days in CXCR2 Ϫ/Ϫ thrombi. Late fibrotic maturation of the thrombus was delayed in the CXCR2 Ϫ/Ϫ mice, with significantly decreased 8 day MMP-2 activity, whereas MMP-9 activity was elevated as compared with controls. Similar impairment in DVT resolution was found at 8 days with anti-CXCR2 inhibition. However, systemic neutropenia, unlike CXCR2 deletion, did not increase the thrombus size as compared with controls.
Pharmacological Inhibition of the Chemokine Receptor, CX3CR1, Reduces Atherosclerosis in Mice
Arteriosclerosis, Thrombosis, and Vascular Biology, 2013
Objective-Alterations of the chemokine receptor CX3CR1 gene were associated with a reduced risk of myocardial infarction in human and limited atherosclerosis in mice. In this study, we addressed whether CX3CR1 antagonists are potential therapeutic tools to limit acute and chronic inflammatory processes in atherosclerosis. Approach and Results-Treatment with F1, an amino terminus-modified CX3CR1 ligand endowed with CX3CR1 antagonist activity, reduced the extent of atherosclerotic lesions in both Apoe −/− and Ldlr −/− proatherogenic mouse models. Macrophage accumulation in the aortic sinus was reduced in F1-treated Apoe −/− mice but the macrophage density of the lesions was similar in F1-treated and control mice. Both in vitro and in vivo F1 treatment reduced CX3CR1-dependent inflammatory monocyte adhesion, potentially limiting their recruitment. In addition, F1-treated Apoe −/− mice displayed reduced numbers of blood inflammatory monocytes, whereas resident monocyte numbers remained unchanged. Both in vitro and in vivo F1 treatment reduced CX3CR1-dependent inflammatory monocyte survival. Finally, F1 treatment of Apoe −/− mice with advanced atherosclerosis led to smaller lesions than untreated mice but without reverting to the initial phenotype.
2000
We have previously shown that members of the ELR ؉ CXC chemokine family, including IL-8; growth-related oncogenes ␣, , and ␥; granulocyte chemotactic protein 2; and epithelial neutrophil-activating protein-78, can mediate angiogenesis in the absence of preceding inflammation. To date, the receptor on endothelial cells responsible for chemotaxis and neovascularization mediated by these ELR ؉ CXC chemokines has not been determined. Because all ELR ؉ CXC chemokines bind to CXC chemokine receptor 2 (CXCR2), we hypothesized that CXCR2 is the putative receptor for ELR ؉ CXC chemokine-mediated angiogenesis. To test this postulate, we first determined whether cultured human microvascular endothelial cells expressed CXCR2. CXCR2 was detected in human microvascular endothelial cells at the protein level by both Western blot analysis and immunohistochemistry using polyclonal Abs specific for human CXCR2. To determine whether CXCR2 played a functional role in angiogenesis, we determined whether this receptor was involved in endothelial cell chemotaxis. We found that microvascular endothelial cell chemotaxis in response to ELR ؉ CXC chemokines was inhibited by anti-CXCR2 Abs. In addition, endothelial cell chemotaxis in response to ELR ؉ CXC chemokines was sensitive to pertussis toxin, suggesting a role for G protein-linked receptor mechanisms in this biological response. The importance of CXCR2 in mediating ELR ؉ CXC chemokine-induced angiogenesis in vivo was also demonstrated by the lack of angiogenic activity induced by ELR ؉ CXC chemokines in the presence of neutralizing Abs to CXCR2 in the rat corneal micropocket assay, or in the corneas of CXCR2 ؊/؊ mice. We thus conclude that CXCR2 is the receptor responsible for ELR ؉ CXC chemokine-mediated angiogenesis.