The Role of YAP/TAZ in von Willebrand Factor Gene Expression

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O'Donnell, Meaghan
YAP , TAZ , von Willebrand Factor , VWF , Shear stress
von Willebrand Factor (VWF) is a large multimeric glycoprotein with important procoagulant roles in the circulation, including mediating platelet adhesion at sites of vascular injury and stabilizing Factor VIII in the plasma. VWF expression and activity is critically regulated to protect against pathological bleeding or thrombotic events, although upstream signals and mechanisms through which VWF gene expression is regulated remain largely unknown. These mechanisms may explain the differential VWF expression observed in different areas of the vasculature with higher synthesis in venous regions. YAP and TAZ are paralogous coactivators largely known for their role in the Hippo pathway. They function predominantly through interactions with TEAD transcription factors to regulate transcription of target genes, which ultimately execute the physiological output of upstream signalling mechanisms. Mechanical signals, such as shear stress, contribute to regulating YAP/TAZ with high shear stress reducing their transcriptional activity. The present work investigates the relationship between YAP/TAZ signalling and the regulation of VWF expression. We show that siRNA-mediated silencing of YAP/TAZ reduces VWF gene expression. We also identified a putative TEAD binding site 224 base pairs upstream of the transcriptional start site and using a VWF promoter reporter construct, we found that absence or alteration of this putative TEAD binding site reduced VWF promoter activity in endothelial cells (ECs). Furthermore, exposure of ECs to varying magnitudes of shear stress affected the phosphorylation and localization of upstream Hippo pathway proteins and VWF gene expression. Cumulatively, these data support a role for YAP/TAZ in regulating VWF gene expression through interactions with TEAD transcription factors, and this may be regulated by upstream mechanical signals such as shear stress.
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