TNF-α-Induced YAP/TAZ Activity Mediates Leukocyte-Endothelial Adhesion by Regulating VCAM1 Expression in Endothelial Cells.

Hyun-Jung Choi,Byeong Kim,Miran Seo,Ji Heo,Na-Eun Kim

doi:10.3390/ijms19113428

Abstract

YAP/TAZ, a transcriptional co-activator of Hippo pathway, has emerged as a central player in vessel homeostasis such as sprouting angiogenesis and vascular barrier stabilization, during development. However, the role of YAP/TAZ in pathological angiogenesis remains unclear. Here, we demonstrated that YAP/TAZ is a critical mediator in leukocyte-endothelial adhesion induced by the vascular inflammatory cytokine TNF-α. YAP/TAZ was dephosphorylated, translocated from the cytosol to the nucleus, and activated by TNF-α in endothelial cells. A specific inhibitor of Rho GTPases suppressed the TNF-α-induced dephosphorylation of YAP. Knockdown of YAP/TAZ using siRNA significantly reduced the expression of the leukocyte adhesion molecule VCAM1 induced by TNF-α. The adhesion of monocytes to endothelial cells was also markedly reduced by YAP/TAZ silencing. However, knockdown of YAP/TAZ did not affect TNF-α-induced NF-κB signaling. Overall, these results suggest that YAP/TAZ plays critical roles in regulating TNF-α-induced endothelial cell adhesive properties without affecting the NF-κB pathway, and implicate YAP/TAZ as a potential therapeutic target for treating inflammatory vascular diseases.

Highlights

Yes-associated protein (YAP) or its paralog, transcriptional coactivator with a PDZ-binding motif (TAZ; known as WWTR1), is a final effector of the Hippo signaling pathway, which plays central roles in cell proliferation, differentiation, tissue homeostasis, and organ morphogenesis [1,2]
We examined the changes in the intracellular localization of YAP in Human umbilical vein endothelial cells (HUVECs) in response to TNF-α
We further confirmed whether TNF-α induces YAP/TAZ activity by analyzing the transcriptional activity of TEAD-responsive elements, which are known to be bound by the TEAD-YAP/TAZ complex

Summary

Introduction

Yes-associated protein (YAP) or its paralog, transcriptional coactivator with a PDZ-binding motif (TAZ; known as WWTR1), is a final effector of the Hippo signaling pathway, which plays central roles in cell proliferation, differentiation, tissue homeostasis, and organ morphogenesis [1,2]. The critical roles of YAP/TAZ in vascular systems have been demonstrated in studies using mice with endothelial-specific deletion of YAP/TAZ These mutant mice displayed defective vessel development, including hyper-pruned vascular networks, and disrupted vascular integrity in growing retinal and brain vessels [7]. Earlier studies showed that YAP activity can be modulated by endothelial junction stability, and is critically involved in the angiogenesis by endothelial cells [10,11]. Despite these findings, it remains unclear whether YAP/TAZ plays a role in vascular remodeling and angiogenesis, under pathological conditions

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Results

Conclusion