Abstract
Atherosclerosis is a chronic inflammatory disease characterized by extensive remodeling of medium and large-sized arteries. Inward remodeling (=lumen shrinkage) of the vascular walls is the underlying cause for ischemia in target organs. Therefore, inward remodeling can be considered the predominant feature of atherosclerotic pathology. Outward remodeling (=lumen enlargement) is a physiological response compensating for lumen shrinkage caused by neointimal hyperplasia, but as a pathological response to changes in blood flow, outward remodeling leads to substantial arterial wall thinning. Thinned vascular walls are prone to rupture, and subsequent thrombus formation accounts for the majority of acute cardiovascular events. Pathological remodeling is driven by inflammatory cells which induce vascular smooth muscle cells to switch from quiescent to a proliferative and migratory phenotype. After decades of intensive research, the molecular mechanisms of arterial remodeling are starting to unfold. In this mini-review, we summarize the current knowledge of the epigenetic and transcriptional regulation of vascular smooth muscle cell phenotype switching from the contractile to the synthetic phenotype involved in arterial remodeling and discuss potential therapeutic options.
Highlights
Atherosclerosis (AS) is a chronic multifactorial disorder of medium and large-sized arteries characterized by inflammation and lipid deposition within the arterial wall, leading to slowly progressive plaque formation (Incalcaterra et al, 2013; Xu et al, 2018)
DNA methylation is mediated by DNA methyltransferases (DNMTs), which, in vertebrates, covalently bind a methyl group predominantly to the cytosine 5 -carbon in the context of a cytidine phosphate guanosine (CpG) dinucleotide (Xu et al, 2018)
DNA methylation can be reversed by dilution via genome replication without maintenance or inactivation of DNMTs, or by active demethylation facilitated by Teneleven translocation (TET) methylcytosine dioxygenases, which catalyze 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) (Jurkowska et al, 2011)
Summary
Atherosclerosis (AS) is a chronic multifactorial disorder of medium and large-sized arteries characterized by inflammation and lipid deposition within the arterial wall, leading to slowly progressive plaque formation (Incalcaterra et al, 2013; Xu et al, 2018). Lineage-tracing experiments have shown that VSMCs are derived from various distinct progenitor cells in embryogenesis due to which VSMCs typically exhibit lineage-dependent responses to signaling pathways and can have distinct functional characteristics (Basatemur et al, 2019) These experiments demonstrated that VSMCs give rise to diverse cell types within lesions fulfilling positive as well as negative roles in atherogenesis, which has led to significant improvements in understanding the functional consequences of developmental origin, clonality, plasticity, and fate of VSMCs within atherosclerotic plaques (Basatemur et al, 2019). Unlike most cell types, VSMCs are not terminally differentiated and display plasticity in their phenotypes (Babaev et al, 1990), ranging from contractile– quiescent to migratory–proliferative–synthetic and osteogenic, or macrophage-like (Jaminon et al, 2019) Upon vascular disease such as AS, VSMCs transdifferentiate into the synthetic phenotype by downregulation of mature VSMCspecific marker expression (Sobue et al, 1999). Different epigenetic modifications influencing the transition from the contractile to the synthetic VSMC phenotype in arterial remodeling of atherosclerotic lesions will be discussed (Figure 1)
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