Inhibition of α4 integrin and ICAM-1 markedly attenuate macrophage homing to atherosclerotic plaques in ApoE-deficient mice

Abstract

Background-Monocytes/macrophages play a central role in many stages of development of atherosclerotic plaques, including the conversion to an unstable morphology with rupture and fissuring. A better understanding of the mechanism of attachment of monocytes to activated endothelial cells would prove useful in developing strategies aimed at blocking this initial step. Here we describe a novel in vivo model that directly demonstrates homing of macrophages to atherosclerotic plaques. Methods and Results-Macrophages were loaded with fluorescent microspheres and injected intravenously into 40- week-old apolipoprotein E-deficient mice. After 48 hours, labeled macrophages were observed adhering to all stages of atherosclerotic plaques from the early fatty streak to mature calcified lesion. The mean number of macrophages adherent to atherosclerotic plaques located in the proximal 1 mm of the aortic root was quantitated by counting serial frozen sections and found to be 143±17 macrophages per aortic root. Pretreatment of the apolipoprotein E- deficient mice with monoclonal antibodies directed against the α-subunit of the α4β1 integrin and against intracellular cell adhesion molecule (ICAM- 1) reduced macrophage homing by 7.5% and 65%, respectively, as compared with isotype-matched controls (P