Stéphanie Michineau1, Grégory Franck1, Orianne Wagner-Ballon1, Jianping Dai1, Eric Allaire1, Marianne Gervais1. 1. 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.).
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. APPROACH AND 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.
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. APPROACH AND 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: Zhenjie Liu; Stephanie Morgan; Jun Ren; Qiwei Wang; Douglas S Annis; Deane F Mosher; Jing Zhang; Christine M Sorenson; Nader Sheibani; Bo Liu Journal: Circ Res Date: 2015-05-04 Impact factor: 17.367
Authors: María Marcos-Jubilar; Josune Orbe; Carmen Roncal; Florencio J D Machado; José Antonio Rodriguez; Alejandro Fernández-Montero; Inmaculada Colina; Raquel Rodil; Juan C Pastrana; José A Páramo Journal: Life (Basel) Date: 2021-05-01