Epigenetic Control of Smooth Muscle Cell Differentiation and Phenotypic Switching in Vascular Development and Disease

Abstract

The vascular smooth muscle cell (SMC) in adult animals is a highly specialized cell whose principal function is contraction. However, this cell displays remarkable plasticity and can undergo profound changes in phenotype during repair of vascular injury, during remodeling in response to altered blood flow, or in various disease states. There has been extensive progress in recent years in our understanding of the complex mechanisms that control SMC differentiation and phenotypic plasticity, including the demonstration that epigenetic mechanisms play a critical role. In addition, recent evidence indicates that SMC phenotypic switching in adult animals involves the reactivation of embryonic stem cell pluripotency genes and that mesenchymal stem cells may be derived from SMC and/or pericytes. This review summarizes the current state of our knowledge in this field and identifies some of the key unresolved challenges and questions that we feel require further study.

Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection

“…Therefore, macrophage Socs3 seems to regulate the response of VSMCs and tissue repair through macrophage‐VSMC interaction 25. Because phenotypic modulation of VSMCs and transforming growth factor beta signaling are essential for arterial injury repair26, 27 and aortic wall homeostasis,28 aberrant responses of VSMCs and transforming growth factor beta signaling in mSocs3‐KO mice may be involved in the progression from the focal medial disruption to AD, possibly attributed to the failure of repair response. The importance of VSMCs in AD pathogenesis is underscored by the fact that mutations in the contractile proteins of VSMCs predispose patients to AD 1.…”

TNF-α Induces Phenotypic Modulation in Cerebral Vascular Smooth Muscle Cells: Implications for Cerebral Aneurysm Pathology

“…Tumor necrosis factor-alpha treatment in cerebral vascular SMCs resulted in increased binding of SP1 at the promoter region of KLF4 along with increased histone acetylation, both of which are characteristic of promotion of KLF4 gene expression (Supplementary Figure 10). 2 Tumor Necrosis Factor-Alpha Induced Binding of Kruppel-Like Transcription Factor 4 to the Promoter Regions of Smooth Muscle Cell Marker Genes and Myocardin To examine potential direct interactions of KLF4 with the promoter regions of SMC marker genes and myocardin, we performed CHIP assays (Figure 1). Tumor necrosis factor-alpha resulted in increased binding of KLF4 to the promoter regions of SM-a-actin, SM-MHC, and myocardin at 6 hours after treatment in cultured cerebral vascular SMCs (Supplementary Figure 11A).…”

“…Phenotypic modulation of vascular SMCs is known to be important in the pathogenesis of atherosclerosis and other vascular diseases. 1,2 There are well-established regional differences in SMC phenotype at the molecular level among different vascular beds, 4 and little is known about SMC differentiation and phenotypic switching in the cerebral circulation. Accumulating data suggest that SMC phenotypic modulation is involved in the pathogenesis of intracranial aneurysms (IA), 5,6 and progression of atherosclerosis within the aneurysmal sac has correlated with aneurysmal growth and rupture.…”

A bioinformatics method for predicting long noncoding RNAs associated with vascular disease

“…VSMCs' phenotypic transition plays a critical role in angiogenesis and restenosis [21]. During this process, various growth factors and cytokines such as platelet-derived growth factor-BB (PDGF-BB), interleukin-1, tumor necrosis factor α (TNF-α) and fibroblast growth factor (FGF) are markedly increased [22].…”