MEF2 (Myocyte Enhancer Factor 2) Is Essential for Endothelial Homeostasis and the Atheroprotective Gene Expression Program.
MEF2 (Myocyte Enhancer Factor 2) Is Essential for Endothelial Homeostasis and the Atheroprotective Gene Expression Program.
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MEF2（肌细胞增强因子2）是内皮稳态和动脉粥样硬化保护基因表达程序所必需的。
DOI：
10.1161/atvbaha.120.314978
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Schwarz JJ
中科院分区：
文献类型：
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作者：
Lu YW;Martino N;Gerlach BD;Lamar JM;Vincent PA;Adam AP;Schwarz JJ
动脉粥样硬化主要形成在振荡剪切应力区域，而层流剪切应力区域受到保护。这种保护作用部分是通过层流区的内皮细胞表达抗炎和抗血栓形成的基因表达程序。已经确定了将这些不同的流动模式传递到内皮的几种分子途径。我们的目标是确定MEF 2家族转录因子在促进动脉粥样硬化保护内皮中的作用。在这里，我们通过内皮特异性缺失的三个MEF 2因子在内皮，Mef 2a，-c，和-d，MEF 2是血管稳态的关键调节。MEF 2缺乏导致全身性炎症、出血、血小板减少、白细胞增多和快速致死。转录组分析表明，MEF 2是所需的三个途径参与确定内皮细胞的流动反应的正常调节。具体来说，MEF 2是Klf 2和Klf 4表达所需的，Klf 2和Klf 4是促进抗炎和抗血栓内皮所必需的两种部分冗余因子。这一关键要求导致Mef 2a/c/d和Klf 2/4的内皮特异性缺失之间的表型相似性。此外，MEF 2调节Notch家族基因Notch 1、Dll 1和Jag 1的表达，这些基因也促进动脉粥样硬化保护内皮。与这些动脉粥样硬化保护途径相反，MEF 2缺乏通过增加TAZ的量上调动脉粥样硬化促进途径。我们的研究结果表明MEF 2是几种转录因子的关键上游调节因子，这些转录因子负责影响动脉粥样硬化的发展并促进抗炎和抗血栓形成的内皮细胞的基因表达程序。
Atherosclerosis predominantly forms in regions of oscillatory shear stress while regions of laminar shear stress are protected. This protection is partly through the endothelium in laminar flow regions expressing an anti-inflammatory and anti-thrombotic gene expression program. Several molecular pathways transmitting these distinct flow patterns to the endothelium have been defined. Our objective is to define the role of the MEF2 family of transcription factors in promoting an atheroprotective endothelium. Here we show through endothelial-specific deletion of the three MEF2 factors in the endothelium, Mef2a, -c, and -d, that MEF2 is a critical regulator of vascular homeostasis. MEF2 deficiency results in systemic inflammation, hemorrhage, thrombocytopenia, leukocytosis, and rapid lethality. Transcriptome analysis reveals that MEF2 is required for normal regulation of three pathways implicated in determining the flow responsiveness of the endothelium. Specifically, MEF2 is required for expression of Klf2 and Klf4, two partially redundant factors essential for promoting an anti-inflammatory and anti-thrombotic endothelium. This critical requirement results in phenotypic similarities between endothelial-specific deletions of Mef2a/c/d and Klf2/4. In addition, MEF2 regulates the expression of Notch family genes, Notch1, Dll1, and Jag1, that also promote an atheroprotective endothelium. In contrast to these atheroprotective pathways, MEF2 deficiency upregulates an atherosclerosis promoting pathway through increasing the amount of TAZ. Our results implicate MEF2 as a critical upstream regulator of several transcription factors responsible for gene expression programs that affect development of atherosclerosis and promote an anti-inflammatory and anti-thrombotic endothelium.