PDF(Pubmed)
Abstract：
Endothelial cells (ECs) are highly plastic, capable of differentiating into various cell types. Endothelial-to-mesenchymal transition (EndMT) is crucial during embryonic development and contributes substantially to vascular dysfunction in many cardiovascular diseases (CVDs). While targeting EndMT holds therapeutic promise, understanding its mechanisms and modulating its pathways remain challenging. Using single-cell RNA sequencing on three in vitro EndMT models, we identified conserved gene signatures. We validated original regulators in vitro and in vivo during embryonic heart development and peripheral artery disease. EndMT induction led to global expression changes in all EC subtypes rather than in mesenchymal clusters. We identified mitochondrial calcium uptake as a key driver of EndMT; inhibiting mitochondrial calcium uniporter (MCU) prevented EndMT in vitro, and conditional Mcu deletion in ECs blocked mesenchymal activation in a hind limb ischemia model. Tissues from patients with critical limb ischemia with EndMT features exhibited significantly elevated endothelial MCU. These findings highlight MCU as a regulator of EndMT and a potential therapeutic target.
摘要：
内皮细胞（ECs）是高度可塑性的，能够分化成各种细胞类型。内皮间质转化（EndMT）在胚胎发育过程中至关重要，并且在许多心血管疾病（CVD）中对血管功能障碍有很大贡献。虽然靶向EndMT具有治疗前景，理解其机制和调节其途径仍然具有挑战性。在三种体外EndMT模型上使用单细胞RNA测序，我们确定了保守的基因特征.我们在胚胎心脏发育和外周动脉疾病期间在体外和体内验证了原始调节因子。EndMT诱导导致所有EC亚型而不是间充质簇中的整体表达变化。我们确定线粒体钙摄取是EndMT的关键驱动因素；抑制线粒体钙单转体（MCU）在体外阻止EndMT，在后肢缺血模型中，ECs中的条件性Mcu缺失阻断了间充质激活。具有EndMT特征的严重肢体缺血患者的组织表现出明显升高的内皮MCU。这些发现强调了MCU作为EndMT的调节剂和潜在的治疗靶标。
