Targeting smooth muscle cell phenotypic switching in vascular disease

Abstract

Objective The phenotypic plasticity of vascular smooth muscle cells (VSMCs) is central to vessel growth and remodeling, but also contributes to cardiovascular pathologies. New technologies including fate mapping, single cell transcriptomics, and genetic and pharmacologic inhibitors have provided fundamental new insights into the biology of VSMC. The goal of this review is to summarize the mechanisms underlying VSMC phenotypic modulation and how these might be targeted for therapeutic benefit. Methods We summarize findings from extensive literature searches to highlight recent discoveries in the mechanisms underlying VSMC phenotypic switching with particular relevance to intimal hyperplasia. PubMed was searched for publications between January 2001 and December 2020. Search terms included VSMCs, restenosis, intimal hyperplasia, phenotypic switching or modulation, and drug-eluting stents. We sought to highlight druggable pathways as well as recent landmark studies in phenotypic modulation. Results Lineage tracing methods have determined that a small number of mature VSMCs dedifferentiate to give rise to oligoclonal lesions in intimal hyperplasia and atherosclerosis. In atherosclerosis and aneurysm, single cell transcriptomics reveal a striking diversity of phenotypes that can arise from these VSMCs. Mechanistic studies continue to identify new pathways that influence VSMC phenotypic plasticity. We review the mechanisms by which the current drug-eluting stent agents prevent restenosis and note remaining challenges in peripheral and diabetic revascularization for which new approaches would be beneficial. We summarize findings on new epigenetic (DNA methylation/TET methylcytosine dioxygenase 2, histone deacetylation, bromodomain proteins), transcriptional (Hippo/Yes-associated protein, peroxisome proliferator-activity receptor-gamma, Notch), and β3-integrin-mediated mechanisms that influence VSMC phenotypic modulation. Pharmacologic and genetic targeting of these pathways with agents including ascorbic acid, histone deacetylase or bromodomain inhibitors, thiazolidinediones, and integrin inhibitors suggests potential therapeutic value in the setting of intimal hyperplasia. Conclusions Understanding the molecular mechanisms that underlie the remarkable plasticity of VSMCs may lead to novel approaches to treat and prevent cardiovascular disease and restenosis.

JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency

“…Epigenetic modifications influence gene expression by altering chromatin accessibility and play a central role in regulating SMC behavior during vascular development and disease ( 33 , 40 ). However, epigenetic changes that occur in SMCs in the context of elastin deficiency have not been reported to our knowledge.…”

“…Epigenetic modifications influence gene expression by altering chromatin accessibility and play a central role in regulating SMC behavior during physiological and pathological conditions, including several cardiovascular diseases ( 33 ). However, epigenetic regulation in the context of elastin deficiency is previously unexplored, and our data implicate elastin deficiency in modulating the epigenetic landscape of SMCs ( Figure 3 ).…”

“…Our results indicate that elastin depletion results in increased SMC levels of JAG1, the γ-secretase complex, the activated form of NICD3, and downstream target genes. Mechanistically, SMCs lacking elastin have reduced global DNA methylation — an epigenetic mark that drives gene silencing ( 33 , 34 ) — and decreased DNA methyltransferase 1 (DNMT1). In particular, elastin depletion in SMCs decreases DNA methylation mark at the promoters of key NOTCH pathway genes JAG1 and γ-secretase catalytic subunits PSEN1 and PSEN2, facilitating their upregulation.…”

Upregulation of Neogenin-1 by a CREB1-BAF47 Complex in Vascular Endothelial Cells is Implicated in Atherogenesis

“…Hadi et al (2018) have recently reported that activation of Neo-1 in VSMCs causes persistent stimulation of metalloproteinase 3 (MMP3) and consequently aberrant degradation of extracellular matrix leading to the pathogenesis of abdominal aortic aneurysm. Because phenotypic switch of VSMCs is a pathophysiological process shared by atherosclerosis and aneurysm (Chakraborty et al, 2021), it is plausible to speculate that Neo-1 might be upregulated by oxLDL in VSMCs and steer VSMCs to switch from a contractile phenotype to a pro-atherogenic phenotype. Alternatively, several reports have suggested that Neo-1 in the myelocytic compartment can potentially drive a pro-inflammatory response in different tissues (Konig et al, 2012;Mirakaj et al, 2012;Schlegel et al, 2014;Schlegel et al, 2019).…”

Role of Integrins in Modulating Smooth Muscle Cell Plasticity and Vascular Remodeling: From Expression to Therapeutic Implications

“…The transition of SMCs from a “contractile” to a “synthetic” phenotype is known as SMC phenotypic modulation or switching, which contributes to SMC proliferation, and migration, and thereby plays a vital role in the progression of atherosclerosis, in-stent restenosis, and other cardiovascular hyperplastic disorders. Additionally, platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), cytokines, integrins, angiotensin II, nitric oxide, reactive oxygen species, and the components of the extracellular matrix (ECM) are known to modulate SMC phenotype [ 3 , 4 , 5 , 6 ]. These dedifferentiated SMCs re-enter the cell cycle and secrete ECM components, including fibronectin, which contributes to vascular remodeling.…”