Direct demonstration of P-selectin- and VCAM-1-dependent mononuclear cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient mice

Apolipoprotein E-deficient (ApoE(-/-)), mice develop atherosclerotic lesion s throughout the arterial tree, including the carotid bifurcation. Although the expression of adhesion molecules such as ICAM-1, vascular cell adhesio n molecule-1 (VCAM-1), and P-selectin on endothelium that overlie atheroscl erotic plaques has been implicated in monocyte recruitment to developing le sions, monocyte adhesion in atherosclerotic vessels has not been observed d irectly. To investigate which adhesion molecules may be important in monocy te adhesion to atherosclerotic lesions, an isolated mouse carotid artery pr eparation was developed and perfused with mononuclear cells. We show rollin g and attachment of the human monocytic cell line U937 and the mouse monocy te-macrophage cell line P388D1 in carotid arteries from 10- to 12-week-old ApoE(-/-) and C57BU6 wild-type mice fed a Western-type diet (21% fat wt/wt) for 4 to 5 weeks. No rolling was observed in carotid arteries from C57BL/6 or BALB/c wild-type mice fed a chow diet and little was observed in BALB/c mice fed a Western-type diet. This model represents early lesion developme nt as shown by minimal macrophage infiltration in the intima of carotid art eries from ApoE(-/-) mice fed a Western-type diet. Rolling was observed at shear stresses that were characteristic of the low-shear recirculation zone near the carotid bifurcation. Mononuclear cell attachment and rolling were significantly inhibited by monoclonal antibody blockade of P-selectin or i ts leukocyte ligand P-selectin glycoprotein ligand-1. Rolling velocities in creased after monoclonal antibody blockade of mononuclear cell alpha(4)-int egrin or VCAM-1, which indicates that alpha(4)-integrin interacting with VC AM-1 stabilizes rolling interactions and prolongs monocyte transit times.