title: Chemokine (C-X-C motif) receptor 4 blockade by AMD3100 inhibits experimental abdominal aortic aneurysm expansion through anti-inflammatory effects.
abstract: OBJECTIVE
  Inflammation plays a critical role in the development of abdominal aortic aneurysms (AAAs). Because stromal cell-derived factor 1 (SDF-1) is known for its ability to attract inflammatory cells, we investigated whether SDF-1/chemokine (C-X-C motif) receptor 4 (CXCR4) axis is expressed in aneurysmal aortic wall and plays a role in AAA physiopathology and asked whether its blockade modulates AAA formation and expansion.
  
  
  RESULTS
  Quantitative real-time polymerase chain reaction analysis showed that SDF-1α and CXCR4 mRNA levels are increased in both human and CaCl2-induced mouse AAA wall and are positively correlated to the aortic diameter in mice. ELISA quantification and immunostaining demonstrated that, in mice, aortic SDF-1α is rapidly induced during AAA formation, first by apoptotic vascular smooth muscle cells in the injured media and then by adventitial macrophages once AAA is fully established. Using green fluorescent protein-positive (GFP(+/-)) bone marrow transplantation experiments, we demonstrated that aortic SDF-1 overexpression is implicated in the recruitment of bone marrow-derived macrophages within the AAA wall. Furthermore, in mice, blockade of CXCR4 by AMD3100 decreases the infiltration of adventitial macrophages, inhibits AAA formation, and prevents aortic wall destruction. AMD3100 reduces the mRNA levels of MMP-12 and MMP-14 as well as that of inflammatory effectors MCP-1, MIP-1β, MIP-2α, RANTES, IL-1β, IL-6, TNF-α, and E-selectin. Finally, AMD3100 stabilizes the diameter of formed, expanding AAAs in 2 experimental models.
  
  
  CONCLUSIONS
  SDF-1/CXCR4 axis is upregulated in human and mouse AAAs. Blockade of CXCR4 with AMD3100 suppresses AAA formation and progression in two rodent models. Blockade of SDF-1/CXCR4 axis may represent a new strategy to limit progression of small human AAAs.
authors.affiliation: From the CNRS EAC 7054, Centre de Recherches Chirurgicales Dominique Chopin, Faculty of Medicine, Paris-Est Créteil University (UPEC), Créteil, France (S.M., G.F., J.D., E.A., M.G.); and Department of Hematology-Immunology, AP-HP, Henri Mondor Hospital, UPEC, Créteil, France (O.W.-B.).
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Michineau
authors.affiliation: From the CNRS EAC 7054, Centre de Recherches Chirurgicales Dominique Chopin, Faculty of Medicine, Paris-Est Créteil University (UPEC), Créteil, France (S.M., G.F., J.D., E.A., M.G.); and Department of Hematology-Immunology, AP-HP, Henri Mondor Hospital, UPEC, Créteil, France (O.W.-B.).
authors.forename: Grégory
authors.initials: G
authors.lastname: Franck
authors.affiliation: From the CNRS EAC 7054, Centre de Recherches Chirurgicales Dominique Chopin, Faculty of Medicine, Paris-Est Créteil University (UPEC), Créteil, France (S.M., G.F., J.D., E.A., M.G.); and Department of Hematology-Immunology, AP-HP, Henri Mondor Hospital, UPEC, Créteil, France (O.W.-B.).
authors.forename: Orianne
authors.initials: O
authors.lastname: Wagner-Ballon
authors.affiliation: From the CNRS EAC 7054, Centre de Recherches Chirurgicales Dominique Chopin, Faculty of Medicine, Paris-Est Créteil University (UPEC), Créteil, France (S.M., G.F., J.D., E.A., M.G.); and Department of Hematology-Immunology, AP-HP, Henri Mondor Hospital, UPEC, Créteil, France (O.W.-B.).
authors.forename: Jianping
authors.initials: J
authors.lastname: Dai
authors.affiliation: From the CNRS EAC 7054, Centre de Recherches Chirurgicales Dominique Chopin, Faculty of Medicine, Paris-Est Créteil University (UPEC), Créteil, France (S.M., G.F., J.D., E.A., M.G.); and Department of Hematology-Immunology, AP-HP, Henri Mondor Hospital, UPEC, Créteil, France (O.W.-B.).
authors.forename: Eric
authors.initials: E
authors.lastname: Allaire
authors.affiliation: From the CNRS EAC 7054, Centre de Recherches Chirurgicales Dominique Chopin, Faculty of Medicine, Paris-Est Créteil University (UPEC), Créteil, France (S.M., G.F., J.D., E.A., M.G.); and Department of Hematology-Immunology, AP-HP, Henri Mondor Hospital, UPEC, Créteil, France (O.W.-B.).
authors.forename: Marianne
authors.initials: M
authors.lastname: Gervais
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001596:Benzylamines; D016026:Bone Marrow Transplantation; D002122:Calcium Chloride; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D000080027:Cyclams; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006168:Guinea Pigs; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D064593:Heterografts; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D020298:U937 Cells
chemical_list: D000893:Anti-Inflammatory Agents; D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C486264:Cxcr4 protein, rat; D000080027:Cyclams; D006571:Heterocyclic Compounds; D018836:Inflammation Mediators; D019718:Receptors, CXCR4; D049452:Green Fluorescent Proteins; D002122:Calcium Chloride; C088327:plerixafor
keywords: aortic aneurysm, abdominal; chemokine CXCL12; inflammation; pharmacology