Upregulation of VCAM-1 and ICAM-1 at Atherosclerosis-Prone Sites on the Endothelium in the ApoE-Deficient Mouse

Abstract

Abstract-Focal recruitment of monocytes and lymphocytes is one of the earliest detectable cellular responses in the formation of lesions of atherosclerosis. This localized accumulation of leukocytes is a multistep process in which the endothelium remains intact and may regulate leukocyte recruitment by expressing specific adhesion molecules. To examine the relationship of adhesion molecule expression to initiation factors and the sites of lesion formation, we analyzed the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and platelet-endothelial cell adhesion molecule-1 (PECAM-1) en face on the aortic endothelium of control mice and homozygous apolipoprotein E-deficient (ApoE Ϫ/Ϫ) mice that develop complex lesions of atherosclerosis similar to those in humans. In control mice, VCAM-1 staining was weak and limited to sites of altered blood flow. In contrast, in the ApoE Ϫ/Ϫ mice, VCAM-1 appeared to be localized over the surface of groups of endothelial cells in lesion-prone sites. Expression of VCAM-1 preceded lesion formation, and increased expression above control levels appeared to be correlated with the extent of exposure to plasma cholesterol. Although ICAM-1 was the most prominent adhesion molecule in lesion-prone sites, its expression appeared to be independent of plasma cholesterol levels and was upregulated in both ApoE Ϫ/Ϫ and control mice. At lesion-prone sites associated with altered blood flow, ICAM-1 was located over the surface of each endothelial cell and on microvilli, whereas VCAM-1 was confined to the cell periphery in non-lesion-prone sites. PECAM-1 was localized at the cell periphery throughout the aorta, and its expression did not appear to be regulated. Thus, the levels, localization, and characteristics of expression of VCAM-1, ICAM-1, and PECAM-1 appear to be differentially regulated. Upregulation of VCAM-1 and ICAM-1 is associated with sites of lesion formation. (Arterioscler Thromb Vasc Biol. 1998;18:842-851.)

Modulation of Expression of Endothelial Intercellular Adhesion Molecule-1, Platelet–Endothelial Cell Adhesion Molecule-1, and Vascular Cell Adhesion Molecule-1 in Aortic Arch Lesions of Apolipoprotein E–Deficient Compared With Wild-Type Mice

“…28 Our results are supported by a recent study that used qualitative analysis and reported increased ICAM-1 expression in apoE-deficient animals. 29 Moreover, and very significantly, observations made on human coronar- ies and carotids show ICAM-1 expression to be correlated with vascular lesions. 7 ICAM-1, as well as VCAM-1, is expressed in a flow-dependent manner.…”

ICAM-1 Deficiency Reduces Atherosclerotic Lesions in Double-Knockout Mice (ApoE − /− /ICAM-1 − /− ) Fed a Fat or a Chow Diet

“…39 Recent qualitative and quantitative data report a significant increase in ICAM-1 expression in the ApoE-deficient mouse. 20,21 Moreover, and very significantly, observations made on human coronaries and carotids show ICAM-1 expression correlated to vascular lesions. 9 ICAM-1 as well as VCAM-1 are expressed in a flow-dependent manner.…”

“…However, qualitative and quantitative increases in endothelial ICAM-1 expression in ApoE-deficient mice are observed. 20,21 Moreover, an anti-ICAM-1 monoclonal antibody in ApoE Ϫ/Ϫ mice greatly reduced the homing of monocytes to sites of atherosclerotic lesions. 22 Finally, ICAM-1 knockout in a C57BL6 fat-fed model greatly reduced the size of vascular lesions.…”

Inhibition of atherosclerosis in apolipoprotein-E-deficient mice following muscle transduction with adeno-associated virus vectors encoding human apolipoprotein-E

“…Gene Therapy smooth muscle cell proliferation, 49 suppression of vascular cell adhesion molecule-1 (VCAM-1) that is involved in the recruitment of monocytes to the site of lesion development, 50 and anti-oxidant activity that prevents the formation of oxidised LDL, which is a major factor in foam cell formation. 14,51 The significant reduction in lesion development of animals treated with rAAV/apoE3 compared with those treated with rAAV/apoE2, may reflect the association of apoE2 with type III hyperlipoproteinaemia, where individuals homozygous for apoE2 are prone to developing premature atherosclerosis.…”