Genetic deletion or antibody blockade of alpha1beta1 integrin induces a stable plaque phenotype in ApoE-/- mice.

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 alpha1beta1 in atherosclerosis. METHODS AND
RESULTS: ApoE-/- mice were alpha1-deficient or received early or delayed anti-alpha1 antibody treatment. Deficiency in alpha1 integrin reduced the area of atherosclerotic plaques and altered plaque composition by reducing inflammation and increasing extracellular matrix. In advanced plaques, alpha1-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-alpha1 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 alpha1-deficient macrophages on collagen I and IV substrata revealed that alpha1-deficient cells can migrate on collagen I, but not IV. Anti-alpha1 antibody treatment of ApoE-/- macrophages also inhibited migration of cells on collagen IV.
CONCLUSIONS: Our results suggest that alpha1beta1 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.