© 2000 American Heart Association, Inc.
Integrative Physiology |
Role of Vascular Cell Adhesion Molecule-1 and Fibronectin Connecting Segment-1 in Monocyte Rolling and Adhesion on Early Atherosclerotic Lesions
From the Department of Biomedical Engineering, University of Virginia, Health Science Center, Charlottesville, Va.
Correspondence to Klaus Ley, MD, Department of Biomedical Engineering, University of Virginia, Box 377, Health Science Center, Charlottesville, VA 22908. E-mail kfl3f{at}virginia.edu
Abstract—Atherosclerotic lesion
development seems to be inflammatory in nature and involves the
recruitment of monocytes to the vessel wall. In this study, we
investigated the role of vascular cell adhesion molecule-1 (VCAM-1) and
fibronectin (FN) connecting segment-1 containing the amino acid
sequence ILDV as functional ligands for
4ß1 integrin (VLA-4) in monocyte rolling
and adherence to early atherosclerotic lesions. Carotid arteries of
apolipoprotein E–deficient mice were isolated and perfused with
monocytes or U937 cells. Cell adhesion was reduced 95±4% by
monoclonal antibodies HP1/2 and HP2/1, which block VLA-4 binding to
both VCAM-1 and FN connecting segment-1. mAb HP1/3 preferentially
blocked interaction of VLA-4 with FN but not VCAM-1 and decreased
adhesion by 30±8%. In contrast, blocking VCAM-1 by perfusing the
isolated carotid artery with mAb MK-2.7 reduced adhesion by 75±12%.
Mononuclear cell adhesion to the early atherosclerotic
endothelium was inhibited by 68±10% in the presence
of EILDVPST but not in the presence of control peptide EIDVLPST. When
VLA-4 or VCAM-1 was blocked, more mononuclear cells rolled on early
lesions at significantly higher (approximately doubled) rolling
velocities. These data demonstrate that (1) blockade of VCAM-1 can
abrogate the majority (75±12%) of VLA-4–dependent monocyte adhesion
on early atherosclerotic endothelia and (2) ILDV peptide interferes
with VLA-4 binding to both VCAM-1 and FN and may be useful in limiting
monocyte adhesion to atherosclerotic lesions. (Circ
Res. 2000;87:153-159.)
Key Words: atherosclerosis • monocyte • fibronectin • connecting segment-1 • vascular cell adhesion molecule-1
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