Abstract
Inflammation in de-endothelialised arteries contributes to the development of cardiovascular diseases. The process that initiates this inflammatory response is the adhesion of monocytes/macrophages to exposed vascular smooth muscle cells, typically stimulated by cytokines such as tumour necrosis factor-α (TNF). The aim of this study was to determine the effect of the sphingolipid sphingosylphosphorylcholine (SPC) on the interaction of monocytes/macrophages with vascular smooth muscle cells. Rat aortic smooth muscle cells and rat bone marrow-derived macrophages were co-cultured using an in vitro assay following incubation with sphingolipids to assess inter-cellular adhesion. We reveal that SPC inhibits the TNF-induced adhesion of macrophages to smooth muscle cells. This anti-adhesive effect was the result of SPC-induced changes to the smooth muscle cells (but not the macrophages) and was mediated, at least partly, via the sphingosine 1-phosphate receptor subtype 2. Lipid raft domains were also required. Although SPC did not alter expression or membrane distribution of the adhesion proteins intercellular adhesion molecule-1 and vascular cellular adhesion protein-1 in smooth muscle cells, SPC preincubation inhibited the TNF-induced increase in inducible nitric oxide synthase (NOS2) resulting in a subsequent decrease in nitric oxide production. Inhibiting NOS2 activation in smooth muscle cells led to a decrease in the adhesion of macrophages to smooth muscle cells. This study has therefore delineated a novel pathway which can inhibit the interaction between macrophages and vascular smooth muscle cells via SPC-induced repression of NOS2 expression. This mechanism could represent a potential drug target in vascular disease.
Highlights
Mononuclear cell adhesion to endothelial cells and their subsequent infiltration into the vascular wall is an important initiating event in the development of atherosclerosis and in blood vessel re-occlusion following angioplasty [1,2]
While research has focussed on the mechanisms of monocyte/macrophage adhesion to endothelial cells, relatively little attention has been paid to interaction of monocyte/macrophage with vascular smooth muscle cells (SMC)
To assess macrophage adhesion to vascular SMC, we used a co-culture model consisting of a 15 min incubation of primary cultured rat aortic SMC and rat bone marrow-derived macrophages (BMDM)
Summary
Mononuclear cell adhesion to endothelial cells and their subsequent infiltration into the vascular wall is an important initiating event in the development of atherosclerosis and in blood vessel re-occlusion (restenosis) following angioplasty [1,2]. Following adhesion to endothelial cells, tissue infiltration of monocytes and their subsequent differentiation to macrophages lead to a local inflammatory response which drives the development of vascular disease [5]. This consists of changes in the vascular SMC phenotype from a quiescent to a more proliferative and. Proliferating neointimal vascular SMC, resulting from vascular injury and endothelial denudation, display an increased binding of monocytes [10] This evidence demonstrates that monocytes/macrophages can adhere to vascular SMC, but that this interaction may be an integral part of vascular disease pathogenesis
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