Vascular smooth muscle cells (VSMCs) are a major cell type present at all stages in atherosclerotic plaques. According to the 'response to injury' and 'vulnerable plaque' hypotheses, contractile VSMCs recruited from the media undergo phenotypic conversion to proliferative synthetic cells that elaborate extracellular matrix to form the fibrous cap and hence stabilise plaques. However, recent lineage tracing studies have highlighted flaws in the interpretation of former studies, revealing these to have underestimated both the content and functions of VSMCs in plaques, and have thus challenged our view on the role of VSMCs in atherosclerosis. It is now evident that VSMCs are even more plastic than previously recognised, and can adopt alternative phenotypes including cells resembling foam cells, macrophages, mesenchymal stem cells, and osteochondrogenic cells, which could contribute both positively and negatively to disease progression. In this review, we present the evidence for VSMC plasticity and summarise the roles of VSMCs and VSMC-derived cells in atherosclerotic plaque development and progression. Correct attribution and spatio-temporal resolution of clinically beneficial and detrimental processes will underpin the success of any therapeutic intervention aimed at VSMCs and their derivatives.

We have investigated the mechanism by which deregulated expression of c‐Myc induces death by apoptosis in serum‐deprived fibroblasts. We demonstrate that Myc‐induced apoptosis in low serum is inhibited by a restricted group of cytokines, principally the insulin‐like growth factors and PDGF. Cytokine‐mediated protection from apoptosis is not linked to the cytokines’ abilities to promote growth. Protection from apoptosis is evident in the post‐commitment (mitogen‐independent) S/G2/M phases of the cell cycle and also in cells that are profoundly blocked in cell cycle progression by drugs. Moreover, IGF‐I inhibition of apoptosis occurs in the absence of protein synthesis, and so does not require immediate early gene expression. We conclude that c‐Myc‐induced apoptosis does not result from a conflict of growth signals but appears to be a normal physiological aspect of c‐Myc function whose execution is regulated by the availability of survival factors. We discuss the possible implications of these findings for models of mammalian cell growth in vivo.

Abstract-The mechanisms involved in the initiation of vascular calcification are not known, but matrix vesicles, the nucleation sites for calcium crystal formation in bone, are likely candidates, because similar structures have been found in calcified arteries. The regulation of matrix vesicle production is poorly understood but is thought to be associated with apoptotic cell death. In the present study, we investigated the role of apoptosis in vascular calcification. We report that apoptosis occurs in a human vascular calcification model in which postconfluent vascular smooth muscle cell (VSMC) cultures form nodules spontaneously and calcify after Ϸ28 days. Apoptosis occurred before the onset of calcification in VSMC nodules and was detected by several methods, including nuclear morphology, the TUNEL technique, and external display of phosphatidyl serine. Inhibition of apoptosis with the caspase inhibitor ZVAD.fmk reduced calcification in nodules by Ϸ40%, as measured by the cresolphthalein method and alizarin red staining. In addition, when apoptosis was stimulated in nodular cultures with anti-Fas IgM, there was a 10-fold increase in calcification.

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