Endothelial-to-mesenchymal transition drives atherosclerosis progression
Endothelial-to-mesenchymal transition drives atherosclerosis progression
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DOI：
10.1172/jci82719
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发表时间：
2015-12-01
影响因子：
15.9
通讯作者：
Simons, Michael
中科院分区：
文献类型：
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作者：
Chen, Pei-Yu;Qin, Lingfeng;Simons, Michael
负责动脉粥样硬化病变的发展和进展的分子机制尚未完全建立。在这里，我们研究了内皮细胞间质转化（EndMT）及其关键调节因子FGF受体1（FGFR 1）在动脉粥样硬化中的作用。在培养的人内皮细胞中，炎性细胞因子和振荡剪切应力均降低内皮FGFR 1表达并激活TGF-β信号传导。我们通过在动脉粥样硬化（Apoe（-/-））小鼠中引入FGF受体底物2 α（Frs 2 α）的内皮特异性缺失，进一步探讨了FGF内皮信号传导中断与动脉粥样硬化进展之间的联系。当被置于高脂肪饮食中时，与Apoe（-/-）小鼠相比，这些双敲除小鼠在更早的时间点发生动脉粥样硬化，最终显示总斑块负荷增加84%。此外，这些动物表现出EndMT的广泛发展、纤连蛋白沉积和新生内膜形成增加。此外，我们对43例不同程度冠心病患者的左主干冠状动脉进行了分子和形态学检查，以评估这些发现的临床相关性。该患者组的冠状动脉粥样硬化程度与内皮FGFR 1表达丧失、内皮TGF-β信号传导激活和EndMT程度密切相关。这些数据证明了保护性内皮FGFR信号传导的丧失、EndMT的发展和动脉粥样硬化进展之间的联系。
The molecular mechanisms responsible for the development and progression of atherosclerotic lesions have not been fully established. Here, we investigated the role played by endothelial-to-mesenchymal transition (EndMT) and its key regulator FGF receptor 1 (FGFR1) in atherosclerosis. In cultured human endothelial cells, both inflammatory cytokines and oscillatory shear stress reduced endothelial FGFR1 expression and activated TGF-beta signaling. We further explored the link between disrupted FGF endothelial signaling and progression of atherosclerosis by introducing endothelial-specific deletion of FGF receptor substrate 2 alpha (Frs2 alpha) in atherosclerotic (Apoe(-/-)) mice. When placed on a high-fat diet, these double-knockout mice developed atherosclerosis at a much earlier time point compared with that their Apoe(-/-) counterparts, eventually demonstrating an 84% increase in total plaque burden. Moreover, these animals exhibited extensive development of EndMT, deposition of fibronectin, and increased neointima formation. Additionally, we conducted a molecular and morphometric examination of left main coronary arteries from 43 patients with various levels of coronary disease to assess the clinical relevance of these findings. The extent of coronary atherosclerosis in this patient set strongly correlated with loss of endothelial FGFR1 expression, activation of endothelial TGF-beta signaling, and the extent of EndMT. These data demonstrate a link between loss of protective endothelial FGFR signaling, development of EndMT, and progression of atherosclerosis.