TY - JOUR
T1 - Genetic deletion or antibody blockade of α1β1 integrin induces a stable plaque phenotype in ApoE-/- mice
AU - Schapira, Kitty
AU - Lutgens, Esther
AU - De Fougerolles, Antonin
AU - Sprague, Andrew
AU - Roemen, Anouk
AU - Gardner, Humphrey
AU - Koteliansky, Victor
AU - Daemen, Mat
AU - Heeneman, Sylvia
PY - 2005/9
Y1 - 2005/9
N2 - Objective - Adhesive interactions between cells and the extracellular matrix play an important role in inflammatory diseases like atherosclerosis. We investigated the role of the collagen-binding integrin α1β1 in atherosclerosis. Methods and Results - ApoE-/- mice were α1-deficient or received early or delayed anti-α1 antibody treatment. Deficiency in α1 integrin reduced the area of atherosclerotic plaques and altered plaque composition by reducing inflammation and increasing extracellular matrix. In advanced plaques, α1-deficient mice had a reduced macrophage and CD3+ cell content, collagen and smooth muscle cell content increased, lipid core sizes decreased, and cartilaginous metaplasia occurred. Anti-α1 antibody treatment reduced the macrophage content in initial plaques after early and delayed treatment, decreased the CD3+ cell content in advanced plaques after delayed treatment, and increased the collagen content in initial and advanced plaques after delayed treatment. Migration assays performed on α1-deficient macrophages on collagen I and IV substrata revealed that α1-deficient cells can migrate on collagen I, but not IV. Anti-α1 antibody treatment of ApoE-/- macrophages also inhibited migration of cells on collagen IV. Conclusions - Our results suggest that α1β1 integrin is involved in atherosclerosis by mediating the migration of leukocytes to lesions by adhesion to collagen IV. Blocking this integrin reduces atherosclerosis and induces a stable plaque phenotype.
AB - Objective - Adhesive interactions between cells and the extracellular matrix play an important role in inflammatory diseases like atherosclerosis. We investigated the role of the collagen-binding integrin α1β1 in atherosclerosis. Methods and Results - ApoE-/- mice were α1-deficient or received early or delayed anti-α1 antibody treatment. Deficiency in α1 integrin reduced the area of atherosclerotic plaques and altered plaque composition by reducing inflammation and increasing extracellular matrix. In advanced plaques, α1-deficient mice had a reduced macrophage and CD3+ cell content, collagen and smooth muscle cell content increased, lipid core sizes decreased, and cartilaginous metaplasia occurred. Anti-α1 antibody treatment reduced the macrophage content in initial plaques after early and delayed treatment, decreased the CD3+ cell content in advanced plaques after delayed treatment, and increased the collagen content in initial and advanced plaques after delayed treatment. Migration assays performed on α1-deficient macrophages on collagen I and IV substrata revealed that α1-deficient cells can migrate on collagen I, but not IV. Anti-α1 antibody treatment of ApoE-/- macrophages also inhibited migration of cells on collagen IV. Conclusions - Our results suggest that α1β1 integrin is involved in atherosclerosis by mediating the migration of leukocytes to lesions by adhesion to collagen IV. Blocking this integrin reduces atherosclerosis and induces a stable plaque phenotype.
KW - Atherosclerosis
KW - Collagen
KW - Extracellular matrix
KW - Integrin
KW - Macrophages
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U2 - 10.1161/01.ATV.0000174807.90292.2f
DO - 10.1161/01.ATV.0000174807.90292.2f
M3 - Article
C2 - 15976328
AN - SCOPUS:24144503329
SN - 1079-5642
VL - 25
SP - 1917
EP - 1924
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 9
ER -