Dichotomous Roles of Smooth Muscle Cell-Derived MCP1 (Monocyte Chemoattractant Protein 1) in Development of Atherosclerosis.

Smooth muscle cells in atherosclerotic plaque take on multiple non-classical phenotypes that may affect plaque stability and therefore the likelihood of myocardial infarction or stroke. However, the mechanisms by which these cells affect stability are only beginning to be explored. In this study, we investigated the contribution of inflammatory MCP1 produced by both classical Myh11+ smooth muscle cells and smooth muscle cells that have transitioned through an Lgals3+ state in atherosclerosis using smooth muscle lineage-tracing mice that label all Myh11+ cells and a dual lineage tracing system that targets Lgals3-transitioned SMC only. We show that loss of MCP1 in all Myh11+ smooth muscle results in a paradoxical increase in plaque size and macrophage content, driven by a baseline systemic monocytosis early in atherosclerosis pathogenesis. In contrast, knockout of MCP1 in Lgals3-transitioned smooth muscle cells using a complex dual lineage-tracing system resulted in lesions with an increased Acta2+ fibrous cap and decreased investment of Lgals3-transitioned smooth muscle cells, consistent with increased plaque stability. Finally, using flow cytometry and single-cell RNAseq, we show that MCP1 produced by Lgals3-transitioned smooth muscle cells influences multiple populations of inflammatory cells in late stage plaques. MCP1 produced by classical smooth muscle cells influences monocyte levels beginning early in disease and was atheroprotective, while MCP1 produced by the Lgals3-transitioned subset of smooth muscle cells exacerbated plaque pathogenesis in late stage disease. Results are the first to determine the function of Lgals3-transitioned inflammatory smooth muscle cells in atherosclerosis and highlight the need for caution when considering therapeutic interventions involving MCP1.

动脉粥样硬化斑块中的平滑肌细胞呈现多种非经典表型，这可能影响斑块稳定性，进而影响心肌梗死或中风的可能性。然而，这些细胞影响稳定性的机制才刚刚开始被探究。 在这项研究中，我们利用标记所有Myh11⁺细胞的平滑肌谱系追踪小鼠以及仅针对Lgals3转化的平滑肌细胞的双谱系追踪系统，研究了经典的Myh11⁺平滑肌细胞以及在动脉粥样硬化过程中经历Lgals3⁺状态转化的平滑肌细胞所产生的炎症性MCP1在动脉粥样硬化中的作用。 我们发现，在动脉粥样硬化发病早期，由于基线全身性单核细胞增多，所有Myh11⁺平滑肌中MCP1的缺失会导致斑块大小和巨噬细胞含量反常增加。相比之下，使用复杂的双谱系追踪系统敲除Lgals3转化的平滑肌细胞中的MCP1，会导致病变处Acta2⁺纤维帽增加以及Lgals3转化的平滑肌细胞减少，这与斑块稳定性增加是一致的。最后，通过流式细胞术和单细胞RNA测序，我们发现Lgals3转化的平滑肌细胞产生的MCP1会影响晚期斑块中多种炎症细胞群。 经典平滑肌细胞产生的MCP1在疾病早期就影响单核细胞水平，具有抗动脉粥样硬化作用，而Lgals3转化的平滑肌细胞亚群产生的MCP1会加剧晚期疾病的斑块发病机制。这些结果首次确定了Lgals3转化的炎症性平滑肌细胞在动脉粥样硬化中的功能，并强调在考虑涉及MCP1的治疗干预时需要谨慎。