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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1917.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Genetic Deletion or Antibody Blockade of 1ß1 Integrin Induces a Stable Plaque Phenotype in ApoE–/– Mice

Kitty Schapira; Esther Lutgens; Antonin de Fougerolles; Andrew Sprague; Anouk Roemen; Humphrey Gardner; Victor Koteliansky; Mat Daemen; Sylvia Heeneman

From the Department of Pathology (K.S., E.L., A.R., M.D., S.H.), Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, The Netherlands; and Biogen Idec (A.d.F., A.S., H.G., V.K.) and Alnylam Pharmaceuticals (A.d.F., A.S., V.K.), Cambridge, Mass.

Correspondence to S. Heeneman, PhD, Department of Pathology, P. Debeyelaan 25, 6229 HX Maastricht, The Netherlands. E-mail sheen{at}lpat.azm.nl

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 1ß1 in atherosclerosis.

Methods and Results— ApoE–/– mice were 1-deficient or received early or delayed anti-1 antibody treatment. Deficiency in 1 integrin reduced the area of atherosclerotic plaques and altered plaque composition by reducing inflammation and increasing extracellular matrix. In advanced plaques, 1-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-1 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 1-deficient macrophages on collagen I and IV substrata revealed that 1-deficient cells can migrate on collagen I, but not IV. Anti-1 antibody treatment of ApoE–/– macrophages also inhibited migration of cells on collagen IV.

Conclusions— Our results suggest that 1ß1 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.

The role of 1ß1 integrin was investigated in atherosclerosis. 1ß1 integrin is involved in atherosclerosis by mediating the migration of leukocytes to lesions via adhesion to collagen IV. Blocking this integrin reduces atherosclerosis and induces a more stable plaque phenotype.

Key Words: atherosclerosis • macrophages • extracellular matrix • collagen • integrin

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