Targeting smooth muscle cell phenotypic switching in vascular disease.
Targeting smooth muscle cell phenotypic switching in vascular disease.
复制标题
DOI：
10.1016/j.jvssci.2021.04.001
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Martin KA
中科院分区：
文献类型：
--
作者：
Chakraborty R;Chatterjee P;Dave JM;Ostriker AC;Greif DM;Rzucidlo EM;Martin KA
血管平滑肌细胞（VSMCs）的表型可塑性对血管生长和重塑至关重要，但也会导致心血管疾病。包括命运图谱、单细胞转录组学以及基因和药物抑制剂在内的新技术为VSMC生物学提供了根本性的新见解。本综述的目的是总结VSMC表型调节的潜在机制以及如何针对这些机制进行治疗获益。
我们总结了广泛文献检索的结果，以强调在与内膜增生特别相关的VSMC表型转换潜在机制方面的最新发现。在PubMed上检索了2001年1月至2020年12月期间的出版物。检索词包括VSMCs、再狭窄、内膜增生、表型转换或调节以及药物洗脱支架。我们试图强调可成药途径以及表型调节方面最近的标志性研究。
谱系追踪方法已经确定，少数成熟的VSMCs去分化，在内膜增生和动脉粥样硬化中产生寡克隆病变。在动脉粥样硬化和动脉瘤中，单细胞转录组学揭示了这些VSMCs可能产生的显著多样的表型。机制研究不断发现影响VSMC表型可塑性的新途径。我们综述了当前药物洗脱支架药物预防再狭窄的机制，并指出在外周和糖尿病血管重建中仍然存在的挑战，对此新的方法将是有益的。我们总结了关于新的表观遗传（DNA甲基化/TET甲基胞嘧啶双加氧酶2、组蛋白去乙酰化、溴结构域蛋白）、转录（Hippo/Yes相关蛋白、过氧化物酶体增殖物激活受体 - γ、Notch）以及β3 - 整合素介导的影响VSMC表型调节的机制的研究结果。用包括抗坏血酸、组蛋白去乙酰化酶或溴结构域抑制剂、噻唑烷二酮类和整合素抑制剂等药物对这些途径进行药理和基因靶向，表明在内膜增生的情况下具有潜在的治疗价值。
了解VSMCs显著可塑性背后的分子机制可能会导致治疗和预防心血管疾病和再狭窄的新方法。
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. 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. 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. Understanding the molecular mechanisms that underlie the remarkable plasticity of VSMCs may lead to novel approaches to treat and prevent cardiovascular disease and restenosis.