Department of Cardiovascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Cells. 2022 Jul 13;11(14):2191. doi: 10.3390/cells11142191.
Shear stress exerted by the blood stream modulates endothelial functions through altering gene expression. KLF2 and KLF4, the mechanosensitive transcription factors, are promoted by laminar flow to maintain endothelial homeostasis. However, how the expression of KLF2/4 is regulated by shear stress is poorly understood. Here, we showed that the activation of PIEZO1 upregulates the expression of KLF2/4 in endothelial cells. Mice with endothelial-specific deletion of exhibit reduced KLF2/4 expression in thoracic aorta and pulmonary vascular endothelial cells. Mechanistically, shear stress activates PIEZO1, which results in a calcium influx and subsequently activation of CaMKII. CaMKII interacts with and activates MEKK3 to promote MEKK3/MEK5/ERK5 signaling and ultimately induce the transcription of . Our data provide the molecular insight into how endothelial cells sense and convert mechanical stimuli into a biological response to promote KLF2/4 expression for the maintenance of endothelial function and homeostasis.
血流产生的切应力通过改变基因表达来调节血管内皮功能。层流促进了机械敏感性转录因子 KLF2 和 KLF4 的表达，从而维持内皮细胞的稳态。然而，切应力如何调节 KLF2/4 的表达还知之甚少。在这里，我们发现 PIEZO1 的激活可上调血管内皮细胞中 KLF2/4 的表达。内皮细胞特异性敲除 的小鼠，其胸主动脉和肺血管内皮细胞中 KLF2/4 的表达减少。在机制上，切应力激活 PIEZO1，导致钙内流，随后激活 CaMKII。CaMKII 与 MEKK3 相互作用并激活 MEKK3，从而促进 MEKK3/MEK5/ERK5 信号通路，并最终诱导 的转录。我们的数据为内皮细胞如何感知和将机械刺激转化为生物反应以促进 KLF2/4 的表达，从而维持内皮功能和稳态提供了分子见解。
