Atherosclerotic Lesions Grow Through Recruitment and Proliferation of Circulating Monocytes in a Murine Model

Abstract

Macrophage-derived foam cells in developing atherosclerotic lesions may potentially originate either from recruitment of circulating monocytes or from migration of resident tissue macrophages. In this study, we have determined the source of intimal macrophages in the apoE-knockout mouse flow-cessation/hypercholesterolemia model of atherosclerosis using a bone marrow transplantation approach. We also examined the time course and spatial distribution of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression to assess whether endothelial adhesion molecules were involved in recruitment of either circulating monocytes or resident macrophages. We used allelic variants of the mouse common leukocyte antigen (CD45) to distinguish host-derived and donor-derived white blood cells (WBCs) both in blood and in macrophage-rich carotid lesions. We found that the distribution of CD45 isoforms in lesions is similar to that of circulating WBCs, whereas the host-type CD45 isoform is more prevalent in resident adventitial macrophages. These data indicate that macrophage-derived foam cells in the lesion derive mainly from circulating precursors rather than from resident macrophages. The corresponding time course of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression suggests that recruitment of circulating WBCs by endothelial adhesion molecules is likely to be more important during lesion initiation than during the later phase of rapid lesion growth. Both in experimental models of atherosclerosis and in human disease, infiltration of macrophages into the arterial intima constitutes one of the earliest cellular events in the development of atherosclerotic lesions. 1-3 Macrophages in the lesion may be derived either from cells already resident in the arterial wall 4 or from circulating monocytes that have undergone diapedesis. Because the mechanisms of cellular recruitment and/or activation are likely to differ depending on the source of the inflammatory cells, determining the relative contribution to lesion growth of cells from these two sources may have important implications in devising successful strategies to slow the growth of lesions.Although much convincing evidence demonstrates the importance of blood-borne monocytes in early lesion development, 1,5,6 the potential contribution of resident macrophages has been more difficult to assess. Experiments involving injection of labeled tracer monocytes can provide estimates for the rate of recruitment of circulating inflammatory cells but do not directly address the issue of mobilization of macrophages already present in arterial tissue. Moreover, alterations in adhesion molecule expression that can occur during monocyte isolation and labeling may modify the interaction between circulating monocytes and the vascular wall. The recent development of a polymerase chain reaction-based method of quantifying monocyte recruitment has shown promise of improved sensitivity and ease of quantitation compared to more traditional approach...

Galectin-3 Gene Inactivation Reduces Atherosclerotic Lesions and Adventitial Inflammation in ApoE-Deficient Mice

“…27 GaL3 was shown to mediate the endocytotic uptake of modified lipoproteins 15 and to be a component of the AGE-receptor complex expressed in macrophages. 16 The functional interaction of GaL3 (AGE-R3) with AGE-R1 and AGE-R2 receptors 28 suggested the possible interaction with AGEbinding proteins.…”

12/15-Lipoxygenase Mediates High-fat Diet-induced Endothelial Tight Junction Disruption and Monocyte Transmigration

“…High-fat Diet-induced EC TJ Disassembly Enhances Monocyte Adhesion-Although endothelial dysfunction marks the initiation of atherosclerosis (26), the recruitment of monocytes to this site "seeds the soil" for the disease pathogenesis (43,44). It has been reported that the areas with endothelial hyperpermeability on the luminal side of the artery recruit circulating monocytes (44).…”

“…It has been reported that the areas with endothelial hyperpermeability on the luminal side of the artery recruit circulating monocytes (44). Based on this information, we applied two approaches to find out whether 12/15-LO-mediated EC TJ disruption results in the recruitment of monocytes.…”

The anti-malarial artemisinin inhibits pro-inflammatory cytokines via the NF-κB canonical signaling pathway in PMA-induced THP-1 monocytes

“…Monocytes/macrophages play important roles in the development of atherosclerosis. Circulating monocytes migrate under the subendothelial space and differentiate into macrophages as a key inflammatory response in the development of atherosclerotic lesions (3,4). As a result of activation, macrophages release a host of pro-inflammatory mediators, including tumor necrosis factor (TNF), interleukins (IL) and several kinds of proteases, such as the matrix metalloproteinases.…”