Targeting smooth muscle cell phenotypic switching in vascular disease

作者：Raja Chakraborty, Payel Chatterjee, Jui M. Dave, Allison C. Ostriker, Daniel M. Greif, Eva M. Rzucidlo, Kathleen A. Martin · 发表于：JVS Vascular Science · 年份：2021 · DOI：10.1016/j.jvssci.2021.04.001 · 被引用次数：189 · 研究领域：Single-cell and spatial transcriptomics、Protein Degradation and Inhibitors、Hippo pathway signaling and YAP/TAZ

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 r...