Endothelial-to-mesenchymal transition shapes the atherosclerotic plaque and modulates macrophage function
Endothelial-to-mesenchymal transition shapes the atherosclerotic plaque and modulates macrophage function
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DOI：
10.1096/fj.201801238r
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发表时间：
2019-02-01
期刊：
影响因子：
4.8
通讯作者：
von Vietinghoff, Sibylle
中科院分区：
文献类型：
--
作者：
Helmke, Alexandra;Casper, Janis;von Vietinghoff, Sibylle
内皮细胞可在刺激后获得间充质表型[内皮-间充质转化（EndMT）]。巨噬细胞聚集在动脉粥样硬化斑块中。本研究探讨了巨噬细胞是否调节EndMT，并描述了EndMT对动脉粥样硬化中巨噬细胞功能的相互作用。在动脉粥样硬化的小鼠和人类动脉粥样硬化中，通过共聚焦显微镜和流式细胞术分析，具有间充质标志物的内皮细胞升高。在这种情况下，EndMT主转录因子Snai 1表达和细胞外基质的增加与EndMT的增强一致。在体内单个主动脉EndMT细胞中检测到缺氧，并在体外快速诱导类似的EndMT表型。巨噬细胞作为一种新型的EndMT诱导剂，在动脉粥样硬化病变中大量存在，在体外共培养过程中可增强间皮细胞标志物的表达。在相反的关系，EndMT改变内皮细胞集落刺激因子的表达。在功能上，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响应氧化LDL的TNF产生，但增加了氧化LDL摄取和清道夫受体表达。这些实验证明巨噬细胞促进部分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形成巨噬细胞和内皮细胞表型，从而除了表面结构外还影响内部动脉粥样硬化斑块。卡斯珀，J.，Nordlohne，J.，大卫，S.，Haller，H.，Zeisberg，E. M.，von Vietinghoff，S.内皮细胞向间充质细胞的转化形成动脉粥样硬化斑块并调节巨噬细胞功能。
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- 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.