Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany.
Department of Cardiology and Pneumology, University Medical Center of Göttingen, Göttingen, Germany.
FASEB J. 2019 Feb;33(2):2278-2289. doi: 10.1096/fj.201801238R. Epub 2018 Sep 27.
Endothelial cells can acquire a mesenchymal phenotype upon irritation [endothelial-to-mesenchymal transition (EndMT)]. Macrophages accumulate in the atherosclerotic plaque. This study addressed whether macrophages modulate EndMT and delineated a reciprocal effect of EndMT on macrophage functions in atherosclerosis. In atherosclerotic murine and human aortas, endothelial cells with mesenchymal markers were elevated by confocal microscopy and flow cytometric analysis. Increased EndMT master transcription factor Snai1 expression and extracellular matrix are consistent with enhanced EndMT in this condition. Hypoxia was detected in individual aortic EndMT cells in vivo and rapidly induced a similar EndMT phenotype in vitro. As a novel inducer of EndMT, macrophages, which are abundant in the atherosclerotic lesions, enhance mesothelial marker expression during coculture in vitro. In the reverse relationship, EndMT altered endothelial colony-stimulating factor expression. Functionally, EndMT cell-conditioned media attenuated macrophage proliferation, antigen-presenting cell marker expression, and TNF-α production in response to oxidized LDL but increased oxidized LDL uptake and scavenger receptor expression. These experiments demonstrate that macrophages promote partial EndMT. In turn, EndMT cells modulate macrophage phenotype and lipid uptake. Our data suggest that EndMT shapes macrophage and endothelial cell phenotypes, thus affecting internal atherosclerotic plaque in addition to surface structure.-Helmke, A., Casper, J., Nordlohne, J., David, S., Haller, H., Zeisberg, E. M., von Vietinghoff, S. Endothelial-to-mesenchymal transition shapes the atherosclerotic plaque and modulates macrophage function.
内皮细胞在受到刺激时可以获得间充质表型[内皮-间充质转化（EndMT）]。巨噬细胞在动脉粥样硬化斑块中积聚。本研究旨在探讨巨噬细胞是否调节 EndMT，并阐明 EndMT 对动脉粥样硬化中巨噬细胞功能的相互影响。在动脉粥样硬化的小鼠和人类主动脉中，通过共聚焦显微镜和流式细胞术分析，内皮细胞中出现了间充质标志物。EndMT 主转录因子 Snai1 表达增加和细胞外基质增加，表明在此条件下 EndMT 增强。在体内单个主动脉 EndMT 细胞中检测到缺氧，并在体外迅速诱导出类似的 EndMT 表型。作为 EndMT 的一种新型诱导剂，富含在动脉粥样硬化病变中的巨噬细胞在体外共培养过程中增强了间充质标志物的表达。在相反的关系中，EndMT 改变了内皮细胞集落刺激因子的表达。功能上，EndMT 细胞条件培养基减弱了巨噬细胞增殖、抗原呈递细胞标志物表达和对氧化型 LDL 的 TNF-α 产生，但增加了氧化型 LDL 的摄取和清道夫受体表达。这些实验表明巨噬细胞促进了部分 EndMT。反过来，EndMT 细胞调节巨噬细胞表型和脂质摄取。我们的数据表明，EndMT 塑造了巨噬细胞和内皮细胞的表型，从而影响了动脉粥样硬化斑块内部，而不仅仅是表面结构。-赫尔姆克，A.，卡斯珀，J.，诺德勒恩，J.，大卫，S.，哈勒，H.，泽斯伯格，E.M.，冯·维廷霍夫，S.内皮-间充质转化塑造了动脉粥样硬化斑块并调节了巨噬细胞功能。
