Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2
Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2
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DOI：
10.1172/jci24787
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发表时间：
2006-01-01
影响因子：
15.9
通讯作者：
Garcia-Cardeña, G
中科院分区：
文献类型：
--
作者：
Parmar, KM;Larman, HB;Garcia-Cardeña, G
面对全身性风险因素，动脉血管系统的某些区域对动脉粥样硬化病变的发展保持相对抵抗力。这些动脉几何形状中的生物力学不同的环境通过内皮衬里的某些关键功能施加保护性影响;然而，导致不同内皮功能表型的特定机械激活转录程序的协调调节的机制仍然难以捉摸。在这里，我们表明，转录因子Kruppel样因子2（KLF 2）的选择性诱导内皮细胞暴露于人颈动脉粥样硬化保护区的生物力学刺激特性，这种流量介导的表达增加发生通过MEKS/ERK 5/MEF 2信号通路。在血流背景下KL 172的过表达和沉默，结合基因表达的全基因组分析结果，表明KL 172的诱导导致控制炎症、血栓形成/止血、血管张力和血管发育的内皮转录程序的协调调节。我们的数据还表明KLF 2表达全面调节IL-1 β介导的内皮活化。因此，KLF 2作为一种机械活化的转录因子，在整合与动脉血管系统区域相关的多种内皮功能中发挥重要作用，这些区域对动脉粥样硬化形成具有相对抗性。
In the face of systemic risk factors, certain regions of the arterial vasculature remain relatively resistant to the development of atherosclerotic lesions. The biomechanically distinct environments in these arterial geometries exert a protective influence via certain key functions of the endothelial lining; however, the mechanisms underlying the coordinated regulation of specific mechano-activated transcriptional programs leading to distinct endothelial functional phenotypes have remained elusive. Here, we show that the transcription factor Kruppel-like factor 2 (KLF2) is selectively induced in endothelial cells exposed to a biomechanical stimulus characteristic of atheroprotected regions of the human carotid and that this flow-mediated increase in expression occurs via a MEKS/ERK5/MEF2 signaling pathway. Overexpression and silencing of KL172 in the context of flow, combined with findings from genome-wide analyses of gene expression, demonstrate that the induction of KL172 results in the orchestrated regulation of endothelial transcriptional programs controlling inflammation, thrombosis/hemostasis, vascular tone, and blood vessel development. our data also indicate that KLF2 expression globally modulates IL-1 beta-mediated endothelial activation. KLF2 therefore serves as a mechano-activated transcription factor important in the integration of multiple endothelial functions associated with regions of the arterial vasculature that are relatively resistant to atherogenesis.