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.