Smooth muscle cell fate and plasticity in atherosclerosis

Abstract

Current knowledge suggests that intimal smooth muscle cells (SMCs) in native atherosclerotic plaque derive mainly from the medial arterial layer. During this process, SMCs undergo complex structural and functional changes giving rise to a broad spectrum of phenotypes. Classically, intimal SMCs are described as dedifferentiated/synthetic SMCs, a phenotype characterized by reduced expression of contractile proteins. Intimal SMCs are considered to have a beneficial role by contributing to the fibrous cap and thereby stabilizing atherosclerotic plaque. However, intimal SMCs can lose their properties to such an extent that they become hard to identify, contribute significantly to the foam cell population, and acquire inflammatory-like cell features. This review highlights mechanisms of SMC plasticity in different stages of native atherosclerotic plaque formation, their potential for monoclonal or oligoclonal expansion, as well as recent findings demonstrating the underestimated deleterious role of SMCs in this disease.

Figure 1

Model of SMC phenotypic diversity in atherosclerotic intima. In humans, medial SMCs migrate into the intima starting in utero in atherosclerosis-prone arteries, forming the DIT layer, likely by monoclonal or oligoclonal expansion. Intimal SMCs can take up lipids to become foam cells, which in vitro data indicate causes a loss of SMC markers and expression of macrophage markers. In addition, SMCs can de-differentiate and express macrophage markers under the influence of factors and epigenetic regulators including PDGF-BB and KLF4. Whether initial lipoprotein loading is required for SMCs to express macrophage markers requires further investigation. It is also not yet known whether SMCs first have to assume a macrophage-like phenotype in order to allow or enhance SMC foam cell formation. SMCs in the fibrous cap that cover the necrotic core have a more differentiated phenotype. Whether some de-differentiated intimal SMCs re-differentiate to supply fibrous cap SMCs remains to be determined.

Figure 2

Schematic model of transcriptional and epigenetic regulation of SMC differentiation markers. In contractile SMCs, the complex MYOCD/SRF binds to CArG box and increases expression of SMC differentiation markers. In contrast, KLF4, a pluripotency transcription factor, absent in contractile SMCs, is increased in intimal SMCs. KLF-4 and ELK-1 bind to G/C repressor element and inhibit the MYOCD/SRF complex leading to decreased expression of SMC differentiation markers. In addition deacetylation of histones by HDAC2 closes chromatin leading to transcriptional repression of SMC differentiation markers. By contrast, DNA demethylation by TET2 increases DNA accessibility to transcription factors resulting in increased SMC differentiation marker expression. (SRF, serum-response factor; MYOCD, Myocardin; KLF 4, Krüppel-like factor 4; ELK1, ETS domain-containing protein-1; CArG, CArG box; G/C rep, G/C repressor elements; HDAC2, histone deacetylase 2; TET2, ten-eleven translocation-2; H, histones; Ac, acetyl group; Me, methyl group).