Aims Cellular communication network factor 2 (CCN2) is a matricellular protein implicated in fibrotic diseases, with ongoing clinical trials evaluating anti-CCN2-based therapies. By uncovering CCN2 as abundantly expressed in non-diseased artery tissue, this study aimed to investigate the hypothesis that CCN2 plays a pivotal role in maintaining smooth muscle cell (SMC) phenotype and protection against atherosclerosis. Methods and results Global- and SMC-specific Ccn2 knockout mouse models were employed to demonstrate that Ccn2 deficiency leads to SMC de-differentiation, medial thickening, and aorta elongation under normolipidaemic conditions. Inducing hyperlipidaemia in both models resulted in severe aorta malformation and a 17-fold increase in atherosclerosis formation. Lipid-rich lesions developed at sites of the vasculature typically protected from atherosclerosis development by laminar blood flow, covering 90% of aortas and extending to other vessels, including coronary arteries. Evaluation at earlier time points revealed medial lipid accumulation as a lesion-initiating event. Fluorescently labelled LDL injection followed by confocal microscopy showed increased LDL retention in the medial layer of Ccn2 knockout aortas, likely attributed to marked proteoglycan enrichment of the medial extracellular matrix. Analyses leveraging data from the Athero-Express study cohort indicated the relevance of CCN2 in established human lesions, as CCN2 correlated with SMC marker transcripts across 654 transcriptomically profiled carotid plaques. These findings were substantiated through in situ hybridization showing CCN2 expression predominantly in the fibrous cap. Conclusion This study identifies CCN2 as a major constituent of the normal artery wall, critical in regulating SMC differentiation and aorta integrity and possessing a protective role against atherosclerosis development. These findings underscore the need for further investigation into the potential effects of anti-CCN2-based therapies on the vasculature.

中文翻译：

---

平滑肌细胞通讯网络因子 2 的缺失导致严重的主动脉畸形和动脉粥样硬化


研究目的 细胞通讯网络因子 2 （CCN2） 是一种与纤维化疾病有关的基质细胞蛋白，正在进行的临床试验正在评估基于抗 CCN2 的疗法。通过发现 CCN2 在非病变动脉组织中大量表达，本研究旨在探讨 CCN2 在维持平滑肌细胞 （SMC） 表型和保护动脉粥样硬化方面起关键作用的假设。方法和结果 采用全局和 SMC 特异性 Ccn2 敲除小鼠模型证明，在正常血量条件下，Ccn2 缺陷导致 SMC 去分化、内侧增厚和主动脉伸长。在两种模型中诱导高脂血症导致严重的主动脉畸形和动脉粥样硬化形成增加 17 倍。在脉管系统部位形成的富含脂质的病变通常通过层状血流保护免受动脉粥样硬化的发展，覆盖 90% 的主动脉并延伸到其他血管，包括冠状动脉。早期时间点的评估显示内侧脂质积累是病变起始事件。荧光标记的 LDL 注射后进行共聚焦显微镜检查显示 LDL 在 Ccn2 敲除主动脉内层的保留增加，这可能归因于内侧细胞外基质的蛋白多糖显着富集。利用 Athero-Express 研究队列数据的分析表明，CCN2 与已确定的人类病变相关，因为 CCN2 与 654 个转录组分析的颈动脉斑块中的 SMC 标志物转录本相关。这些发现通过原位杂交得到证实，显示 CCN2 主要在纤维帽中表达。 结论 本研究确定 CCN2 是正常动脉壁的主要成分，对调节 SMC 分化和主动脉完整性至关重要，并具有防止动脉粥样硬化发展的保护作用。这些发现强调了进一步研究基于抗 CCN2 的疗法对脉管系统的潜在影响的必要性。