Original Contributions |
From the Departments of Biomedical Engineering (C.L.R., Y.H., U.J., S.G., D.R.M., K.L.) and Internal Medicine (I.J.S.), University of Virginia Health Sciences Center, Charlottesville. The current affiliation for C.L.R. is Southwestern Oklahoma State University, School of Pharmacy, Weatherford, Okla.
Correspondence to Klaus Ley, MD, Department of Biomedical Engineering, University of Virginia, Box 377, Health Sciences Center, Charlottesville, VA 22908. E-mail kfl3f{at}virginia.edu
AbstractApolipoprotein
Edeficient (ApoE-/-) mice develop atherosclerotic
lesions throughout the arterial tree, including the carotid
bifurcation. Although the expression of adhesion molecules such as
ICAM-1, vascular cell adhesion molecule-1 (VCAM-1), and P-selectin on
endothelium that overlie atherosclerotic plaques has
been implicated in monocyte recruitment to developing lesions, monocyte
adhesion in atherosclerotic vessels has not been observed directly. To
investigate which adhesion molecules may be important in monocyte
adhesion to atherosclerotic lesions, an isolated mouse carotid artery
preparation was developed and perfused with mononuclear cells. We show
rolling and attachment of the human monocytic cell line U937 and the
mouse monocyte-macrophage cell line P388D1 in carotid arteries
from 10- to 12-week-old ApoE-/- and C57BL/6 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
development as shown by minimal macrophage infiltration in the
intima of carotid arteries 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 its
leukocyte ligand P-selectin glycoprotein ligand-1. Rolling
velocities increased after monoclonal antibody blockade of mononuclear
cell
4-integrin or VCAM-1, which indicates that
4-integrin interacting with VCAM-1 stabilizes rolling
interactions and prolongs monocyte transit times.
Key Words: apolipoprotein rolling selectin monocyte atherosclerosis
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