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Circulation Research. 1999;84:1237-1244

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(Circulation Research. 1999;84:1237-1244.)
© 1999 American Heart Association, Inc.


Original Contributions

Direct Demonstration of P-Selectin– and VCAM-1–Dependent Mononuclear Cell Rolling in Early Atherosclerotic Lesions of Apolipoprotein E–Deficient Mice

Carroll L. Ramos, Yuqing Huo, Unsu Jung, Shukti Ghosh, David R. Manka, Ian J. Sarembock, Klaus Ley

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

Abstract—Apolipoprotein E–deficient (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 {alpha}4-integrin or VCAM-1, which indicates that {alpha}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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CirculationHome page
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Endothelial Dysfunction After Repeated Chlamydia pneumoniae Infection in Apolipoprotein E-Knockout Mice
Circulation, August 29, 2000; 102(9): 1039 - 1044.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
Y. Huo, A. Hafezi-Moghadam, and K. Ley
Role of Vascular Cell Adhesion Molecule-1 and Fibronectin Connecting Segment-1 in Monocyte Rolling and Adhesion on Early Atherosclerotic Lesions
Circ. Res., July 21, 2000; 87(2): 153 - 159.
[Abstract] [Full Text] [PDF]


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BloodHome page
A. E. May, F.-J. Neumann, A. Schomig, and K. T. Preissner
VLA-4 (alpha 4beta 1) engagement defines a novel activation pathway for beta 2 integrin-dependent leukocyte adhesion involving the urokinase receptor
Blood, July 15, 2000; 96(2): 506 - 513.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
F. Mach
Toward New Therapeutic Strategies Against Neointimal Formation in Restenosis
Arterioscler Thromb Vasc Biol, July 1, 2000; 20(7): 1699 - 1700.
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CirculationHome page
Z. M. Dong, A. A. Brown, and D. D. Wagner
Prominent Role of P-Selectin in the Development of Advanced Atherosclerosis in ApoE-Deficient Mice
Circulation, May 16, 2000; 101(19): 2290 - 2295.
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JEMHome page
R. G. Collins, R. Velji, N. V. Guevara, M. J. Hicks, L. Chan, and A. L. Beaudet
P-Selectin or Intercellular Adhesion Molecule (Icam)-1 Deficiency Substantially Protects against Atherosclerosis in Apolipoprotein E-Deficient Mice
J. Exp. Med., January 3, 2000; 191(1): 189 - 194.
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ScienceHome page
K. Node, Y. Huo, X. Ruan, B. Yang, M. Spiecker, K. Ley, D. C. Zeldin, and J. K. Liao
Anti-inflammatory Properties of Cytochrome P450 Epoxygenase-Derived Eicosanoids
Science, August 20, 1999; 285(5431): 1276 - 1279.
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Circ. Res.Home page
D. J. Lefer and D. N. Granger
Monocyte Rolling in Early Atherogenesis : Vital Role in Lesion Development
Circ. Res., June 11, 1999; 84(11): 1353 - 1355.
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Proc. Natl. Acad. Sci. USAHome page
E. Trogan, R. P. Choudhury, H. M. Dansky, J. X. Rong, J. L. Breslow, and E. A. Fisher
Laser capture microdissection analysis of gene expression in macrophages from atherosclerotic lesions of apolipoprotein E-deficient mice
PNAS, February 19, 2002; 99(4): 2234 - 2239.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
H. Chen, D. Li, T. Saldeen, and J. L. Mehta
Transforming Growth Factor-{beta}1 Modulates Oxidatively Modified LDL-Induced Expression of Adhesion Molecules: Role of LOX-1
Circ. Res., December 7, 2001; 89(12): 1155 - 1160.
[Abstract] [Full Text] [PDF]