AIMS Accruing evidence illustrates an emerging paradigm of dynamic vascular smooth muscle cell (SMC) transdifferentiation during atherosclerosis progression. However, the molecular regulators that govern SMC phenotype diversification remain poorly defined. This study aims to elucidate the functional role and underlying mechanisms of cellular communication network factor 2 (CCN2), a matricellular protein, in regulating SMC plasticity in the context of atherosclerosis. METHODS AND RESULTS In both human and murine atherosclerosis, an up-regulation of CCN2 is observed in transdifferentiated SMCs. Using an inducible murine SMC CCN2 deletion model, we demonstrate that SMC-specific CCN2 knockout mice are hypersusceptible to atherosclerosis development as evidenced by a profound increase in lipid-rich plaques along the entire aorta. Single-cell RNA sequencing studies reveal that SMC deficiency of CCN2 positively regulates machinery involved in endoplasmic reticulum stress, endocytosis, and lipid accumulation in transdifferentiated macrophage-like SMCs during the progression of atherosclerosis, findings recapitulated in CCN2-deficient human aortic SMCs. CONCLUSION Our studies illuminate an unanticipated protective role of SMC-CCN2 against atherosclerosis. Disruption of vascular wall homeostasis resulting from vascular SMC CCN2 deficiency predisposes mice to atherosclerosis development and progression.

中文翻译：

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细胞通讯网络因子 2 调节动脉粥样硬化中平滑肌细胞转分化和脂质积累。


目的 越来越多的证据表明动脉粥样硬化进展过程中动态血管平滑肌细胞 (SMC) 转分化的新兴范例。然而，控制 SMC 表型多样化的分子调节因子仍然不明确。本研究旨在阐明细胞通讯网络因子 2 (CCN2)（一种基质细胞蛋白）在调节动脉粥样硬化背景下 SMC 可塑性中的功能作用和潜在机制。方法和结果 在人和小鼠动脉粥样硬化中，在转分化的 SMC 中观察到 CCN2 的上调。使用可诱导的小鼠 SMC CCN2 缺失模型，我们证明 SMC 特异性 CCN2 敲除小鼠对动脉粥样硬化的发展非常敏感，整个主动脉富含脂质的斑块显着增加就证明了这一点。单细胞RNA测序研究表明，在动脉粥样硬化进展过程中，CCN2的SMC缺陷可正向调节涉及内质网应激、内吞作用和转分化巨噬细胞样SMC中脂质积累的机制，这一发现在CCN2缺陷的人主动脉SMC中得到了重现。结论我们的研究阐明了 SMC-CCN2 对动脉粥样硬化的意想不到的保护作用。血管 SMC CCN2 缺陷导致血管壁稳态破坏，使小鼠容易发生动脉粥样硬化。