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

Research output: Contribution to journalArticle

221 Citations (Scopus)

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 α4-integrin or VCAM-1, which indicates that α4-integrin interacting with VCAM-1 stabilizes rolling interactions and prolongs monocyte transit times.

Original languageEnglish (US)
Pages (from-to)1237-1244
Number of pages8
JournalCirculation research
Volume84
Issue number11
DOIs
StatePublished - Jun 11 1999

Fingerprint

P-Selectin
Vascular Cell Adhesion Molecule-1
Apolipoproteins E
Monocytes
Carotid Arteries
Integrins
Macrophages
Monoclonal Antibodies
Cell Line
Atherosclerotic Plaques
Intercellular Adhesion Molecule-1
Endothelium
Leukocytes
Fats
Diet
Ligands
Western Diet

Keywords

  • Apolipoprotein
  • Monocyte atherosclerosis
  • Rolling
  • Selectin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Direct demonstration of P-selectin- and VCAM-1-dependent mononuclear cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient mice. / Ramos, Carroll L.; Huo, Yuqing; Jung, Unsu; Ghosh, Shukti; Manka, David R.; Sarembock, Ian J.; Ley, Klaus.

In: Circulation research, Vol. 84, No. 11, 11.06.1999, p. 1237-1244.

Research output: Contribution to journalArticle

Ramos, Carroll L. ; Huo, Yuqing ; Jung, Unsu ; Ghosh, Shukti ; Manka, David R. ; Sarembock, Ian J. ; Ley, Klaus. / Direct demonstration of P-selectin- and VCAM-1-dependent mononuclear cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient mice. In: Circulation research. 1999 ; Vol. 84, No. 11. pp. 1237-1244.
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AB - 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 α4-integrin or VCAM-1, which indicates that α4-integrin interacting with VCAM-1 stabilizes rolling interactions and prolongs monocyte transit times.

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