Regulation of Macrophage Foam Cell Formation by αVβ3 Integrin

Abstract

The accumulation of macrophage foam cells in atherosclerotic lesions is associated with both initiation and progression of this disease. Scavenger receptors CD36 and SRA are the primary receptors responsible for conversion of macrophages into foam cells. Integrin alphaVbeta3 plays a role in the differentiation of several cell types, but its involvement in the transition of macrophages into foam cells and the potential role of this receptor in atherosclerosis have not been examined. Using an in vitro model of single surface receptor activation by binding with an immobilized monoclonal antibody specific to alphaVbeta3 integrin we show that ligation of alphaVbeta3 integrin prevents differentiation of blood monocytes and macrophages into the foam cell phenotype via coordinate down-regulation of CD36 and SRA. This effect of alphaVbeta3 integrin ligation can be reproduced by contact with endothelial cells, whereas the inhibition of alphaVbeta3 receptor ligation restores the uptake of oxidized low-density lipoprotein. Moreover, we found that alphaVbeta3 integrin is readily detected in situ on macrophages in early and advanced atherosclerotic lesions and that in vitro exposure to oxidized low-density lipoprotein up-regulates alphaVbeta3 integrin expression. We hypothesize that alphaVbeta3 integrin regulates macrophage functional maturation into foam cells in a persistent manner, and therefore, by targeting alphaVbeta3 receptor it could potentially be possible to regulate progression of atherosclerosis in humans.

Fluorescence Reflectance Imaging of Macrophage-Rich Atherosclerotic Plaques Using an αvβ3 Integrin–Targeted Fluorochrome

“…RGD-Cy 5.5 not only strongly stained macrophages but also revealed a weaker signal associated with elastinrich fibers of the medium and vascular SMCs underlying the atherosclerotic plaque. These results were also congruent to the findings of Antonov et al (9), who demonstrated that a v b 3 integrin receptors, compared with endothelial cells, SMCs, and tissue macrophages, were highly upregu- lated in atheroma macrophages of early lipid (fatty streak) and advanced atherosclerotic lesions. However, endothelial cells and SMCs are known to express the vitronectin receptor on their surface (11) and to bind proteolytically active MMP-2, among other ligands.…”

“…Interestingly, monocytederived macrophages express high levels of integrins. Molecular imaging of integrins may, therefore, allow for noninvasive assessment of macrophage infiltration (9). Moreover, integrins constitute an important class of celladhesion receptors responsible not only for cell-matrix and cell-cell adhesion but also for inside-out and outside-in signal transduction.…”

Pro-inflammatory Secretory Phospholipase A2 Type IIA Binds to Integrins αvβ3 and α4β1 and Induces Proliferation of Monocytic Cells in an Integrin-dependent Manner

“…platelet-derived growth factor, fibroblast growth factor). ␣v␤3 is consistently detected on the macrophages in early and advanced human atherosclerotic lesions, and its expression is up-regulated by atherogenic stimuli (oxidized low-density lipoprotein, macrophage colonystimulating factor) in vitro (50). These reports suggest that sPLA2-IIA and ␣v␤3 co-exist in the inflammatory lesion and directly connect the pro-inflammatory action of sPLA2-IIA and ␣v␤3, the newly identified receptor of sPLA2-IIA.…”

Interaction of Monocytes With Vascular Smooth Muscle Cells Regulates Monocyte Survival and Differentiation Through Distinct Pathways

“…Interestingly, a very recent report showed that monocyte CD36 expression and differentiation were downregulated when they bind to endothelial cells. 37 Therefore, binding-mediated monocyte CD36 regulation during cell-cell interactions seems to be cell-type specific, and the subendothelial space could be more favorable than blood vessel lumen for monocyte differentiation.…”