LOCALIZED ADHESION OF MONOCYTES TO HUMAN ATHEROSCLEROTIC PLAQUES DEMONSTRATED IN-VITRO - IMPLICATIONS FOR ATHEROGENESIS

Blood-derived macrophages in the arterial intima are a characteristic feature of active atherosclerotic plaques. Adherent monocytes on the l uminal surface and increased adhesion molecules on the endothelium hav e suggested that specific molecular adhesion mechanisms are involved i n monocyte/macrophage traffic into the arterial wall. Adhesion of huma n monocytes and related cell lines was therefore studied in vitro to h istological sections of human plaques. At 37 degrees C, these cells fo und selectively to the plaques. Binding to the endothelium occurred an d was also present extensively in the diseased intima. Inhibition stud ies showed that the endothelial and general intimal binding had largel y similar molecular proteins. Strong inhibition was produced by antibo dies to the monocyte-specific adhesion molecule CD14, to beta(2) integ rins, and to ICAM-1. Likewise, a peptide containing the Arg-Gly-Asp se quence was strongly inhibitory, suggesting that binding of leukocyte i ntegrins to arterial extracellular matrix was synergistic with cell-ce ll interactions. A P-selectin antibody was exceptional in giving selec tive inhibition of endothelial adhesion, which correlates with the spe cific endothelial localization of this adhesion molecule. These result s show that monocytes adhere to atherosclerotic plaques through the fo cal activation of multiple arterial wall adhesion molecules, confirmin g the adhesion hypothesis. A positive feedback theory for the pathogen esis of atherosclerosis can be suggested, based on the ability of macr ophages in the wall to activate the endothelium, induce adhesion molec ules, and facilitate additional monocyte entry. The adhesion assay pro vides a means for the identification of adhesion inhibitors with thera peutic potential.