YAP promotes endothelial barrier repair by repressing STAT3/VEGF signaling

• Published in: Life sciences (1973) 2020-09, Vol.256, p.117884-117884, Article 117884
• Main Authors: Fan, Xiaofang, Shan, Xiaoqiong, Jiang, Shan, Wang, Sixian, Zhang, Fukun, Tian, Qiuyun, Chen, Danyang, Ma, Jianshe, Xue, Feng, Mao, Sunzhong, Fan, Junming, Wang, Yongyu, Gong, Yongsheng
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Calcium; Calcium permeability; Calcium phosphates; Cell lines; Cell Membrane Permeability - drug effects; Cell permeability; Electrical resistivity; Endothelial barrier; Endothelial barrier repair; Endothelial cells; Gene expression; Hippo-YAP; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Immunofluorescence; Injuries; Medical treatment; Packaging; Permeability; Protein Binding - drug effects; Proteins; Repair; Signal Transduction - drug effects; Stat3 protein; STAT3 Transcription Factor - metabolism; Therapeutic applications; TNF-α; Transcription Factors - metabolism; Transfection; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-α; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Western blotting; Yes-associated protein
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2020.117884

Endothelial barrier dysfunction is associated with multiple diseases, and barrier repair may be a possible therapeutic target. Yes-associated protein and its pathway have been implicated in organ repair after injury. However, the mechanisms underlying barrier repair and any role YAP plays in the process are unclear. This study aimed to explore the role and mechanism of YAP in the repair of endothelial cell permeability after TNF-α-induced injury. A trans-endothelial electrical resistance assay was performed to investigate changes in endothelial cell permeability. Lentivirus packaging by calcium phosphate transfection was used to construct endothelial cell lines with knocked down or overexpressed YAP. Western blotting, immunofluorescence, CO-IP, and real-time PCR were used to detect related protein and gene expression. YAP is involved in the repair process of TNF-α-induced endothelial cell permeability injury; its overexpression promotes repair of endothelial cell permeability, and knockdown weakens repair ability. Moreover, YAP may promote repair by down-regulating STAT3 activity, thereby inhibiting VEGF expression. Elucidating the role of YAP in endothelial cell permeability repair process after injury might reveal mechanisms of endothelial barrier repair and provide therapeutic targets for treatment of vascular hyper-permeability disease. A model of the mechanism by which YAP regulates endothelial permeability repair. TNF-α activates STAT3, which is phosphorylated and polymerized into an activated transcriptional activator in the form of homodimer or heterodimer and enters the nucleus to bind a specific site and promote VEGF transcription. Increased VEGF expression phosphorylates VE-cadherin and disrupts the integrity of the endothelial barrier. TNF-α actives YAP at the same time, and the activated YAP enters the nucleus and interacts with STAT3 to inhibit VEGF expression and promote the process of endothelial barrier repair. [Display omitted]