Mechanosensitive Channel PIEZO1 Senses Shear Force to Induce KLF2/4 Expression via CaMKII/MEKK3/ERK5 Axis in Endothelial Cells
Qi Zheng,
Yonggang Zou,
Peng Teng,
Zhenghua Chen,
Yuefeng Wu,
Xiaoyi Dai,
Xiya Li,
Zonghao Hu,
Shengjun Wu,
Yanhua Xu,
Weiguo Zou,
Hai Song,
Liang Ma
Affiliations
Qi Zheng
Department of Cardiovascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
Yonggang Zou
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
Peng Teng
Department of Cardiovascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
Zhenghua Chen
Department of Cardiovascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
Yuefeng Wu
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
Xiaoyi Dai
Department of Cardiovascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
Xiya Li
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
Zonghao Hu
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
Shengjun Wu
Department of Cardiovascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
Yanhua Xu
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
Weiguo Zou
CAS Center for Excellence in Molecular Cell Sciences, State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Shanghai 200031, China
Hai Song
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
Liang Ma
Department of Cardiovascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
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 Piezo1 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 KLF2/4. 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.
