Taylor James C K, Worssam Matthew D, Oc Sebnem, Lambert Jordi, Mahbubani Krishnaa T, Foote Kirsty, Finigan Allie, Chan Yee-Hung, Figg Nichola, Clarke Murray C H, Bennett Martin R, Jørgensen Helle F
Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute, Papworth Road, Cambridge CB2 0BB, UK.
Functional Gene Control Group, MRC Laboratory of Medical Sciences and Institute of Clinical Sciences, Faculty of Medicine, Imperial College Du Cane Road, London, W12 0NN, UK.
Cardiovasc Res. 2025 Jun 27. doi: 10.1093/cvr/cvaf112.
AIMS: Vascular smooth muscle cells (VSMCs) accumulate in atherosclerotic plaques and exhibit remarkable phenotypic plasticity, contributing to both plaque growth and stability. The plaque-stabilising fibrous cap is rich in VSMC-derived cells, yet the cellular transitions and regulatory mechanisms governing fibrous cap formation remain unclear. Here, we aimed to identify the VSMC phenotypic transitions associated with this critical process. METHODS AND RESULTS: Mapping of lineage-traced VSMCs during plaque development revealed investment of VSMCs prior to fibrous cap formation. Using single-cell RNA-sequencing (scRNA-seq) profiles of lineage-traced VSMCs from atherosclerotic and acutely injured mouse arteries, we identified a disease-specific VSMC state co-expressing contractile genes with extracellular matrix (ECM) components (including fibrillar collagens and elastin) and NOTCH3, which are associated with fibrous cap formation. Computational trajectory analysis predicted that this proposed fibrous cap-related VSMC (fcVSMC) state arises from a previously described plastic, intermediate VSMC population expressing SCA1 and VCAM1. Clonal analysis further showed that NOTCH3+ fcVSMCs derive from intermediate VSMCs in both atherosclerosis and an acute vascular injury model, suggesting a conserved disease-relevant mechanism. The fcVSMCs were enriched in plaque fibrous caps compared to lesion cores, consistent with a role in fibrous cap formation. By combining scRNA-seq trajectory analysis and spatial transcriptomics of human atherosclerotic plaques, we identified protease-activated receptor-1 (PAR1) as a candidate regulator of fcVSMC generation. PAR1 was expressed by VSMCs in human plaque fibrous caps and PAR1 activation by thrombin induced expression of contractile genes and ECM components associated with the fcVSMC state in human VSMCs. CONCLUSIONS: Our findings identify a VSMC transition linked to fibrous cap formation in atherosclerosis and show this is modelled by vascular injury. We identify VSMC-expressed PAR1 as a potential therapeutic target for promoting plaque stability by driving the transition to the matrix-producing, fibrous cap-associated VSMC state.
目的：血管平滑肌细胞（VSMC）在动脉粥样硬化斑块中积聚，并表现出显著的表型可塑性，这对斑块的生长和稳定性都有影响。斑块稳定的纤维帽富含VSMC衍生细胞，但控制纤维帽形成的细胞转变和调节机制仍不清楚。在此，我们旨在确定与这一关键过程相关的VSMC表型转变。 方法与结果：在斑块形成过程中对谱系追踪的VSMC进行定位，发现VSMC在纤维帽形成之前就已参与其中。利用来自动脉粥样硬化和急性损伤小鼠动脉的谱系追踪VSMC的单细胞RNA测序（scRNA-seq）图谱，我们确定了一种疾病特异性的VSMC状态，该状态共表达收缩基因以及细胞外基质（ECM）成分（包括纤维状胶原蛋白和弹性蛋白）和NOTCH3，这些与纤维帽形成相关。计算轨迹分析预测这种提出的与纤维帽相关的VSMC（fcVSMC）状态源自先前描述的表达SCA1和VCAM1的可塑性中间VSMC群体。克隆分析进一步表明，NOTCH3+ fcVSMC在动脉粥样硬化和急性血管损伤模型中均源自中间VSMC，这表明存在一种保守的疾病相关机制。与病变核心相比，fcVSMC在斑块纤维帽中富集，这与它们在纤维帽形成中的作用一致。通过结合scRNA-seq轨迹分析和人类动脉粥样硬化斑块的空间转录组学，我们确定蛋白酶激活受体-1（PAR1）是fcVSMC生成的候选调节因子。PAR1在人类斑块纤维帽中的VSMC中表达，凝血酶激活PAR1可诱导人类VSMC中与fcVSMC状态相关的收缩基因和ECM成分的表达。 结论：我们的研究结果确定了一种与动脉粥样硬化中纤维帽形成相关的VSMC转变，并表明这在血管损伤中得到模拟。我们确定VSMC表达的PAR1是通过驱动向产生基质的、与纤维帽相关的VSMC状态转变来促进斑块稳定性的潜在治疗靶点。
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