INHIBITION OF ALPHA(4) INTEGRIN AND ICAM-1 MARKEDLY ATTENUATE MACROPHAGE HOMING TO ATHEROSCLEROTIC PLAQUES IN APOE-DEFICIENT MICE

Background-Monocytes/macrophages play a central role in many stages of development of atherosclerotic plaques, including the conversion to a n unstable morphology with rupture and fissuring, A better understandi ng of the mechanism of attachment of monocytes to activated endothelia l cells would prove useful in developing strategies aimed at blocking this initial step. Here we describe a novel in vivo model that directl y demonstrates holding of macrophages to atherosclerotic plaques. Meth ods 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 a ll stages of atherosclerotic plaques from the early fatty streak to ma ture calcified lesion. The mean number of macrophages adherent to athe rosclerotic plaques located in the proximal 1 mm of the aortic root wa s 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 alpha-s ubunit of the alpha,beta(1) integrin and against intracellular cell ad hesion molecule (ICAM-1) reduced macrophage homing by 75% and 65%, res pectively, as compared with isotype-matched controls (P<.05). Pretreat ment with a monoclonal antibody directed against E-selectin did not si gnificantly reduce macrophage homing. Conclusions-These data demonstra te that alpha(4) integrin and ICAM-1 play major roles in the recruitme nt of macrophages to atherosclerotic plaques, whereas E-selectin does not appear to contribute significantly to macrophage recruitment. This model will be useful for studying the mechanism of macrophage recruit ment to atherosclerotic plaques and for evaluating the efficacy of inh ibitors to adhesion molecules in preventing macrophage recruitment.