Thromboxane A2 Activates YAP/TAZ Protein to Induce Vascular Smooth Muscle Cell Proliferation and Migration

Xu Feng,Peng Liu,Xin Zhou,Meng-Tian Li,Fu-Long Li,Zhen Wang,Zhipeng Meng,Yi-Ping Sun,Ying Yu,Yue Xiong,Hai-Xin Yuan,Kun-Liang Guan

doi:10.1074/jbc.m116.739722

Abstract

The thromboxane A2 receptor (TP) has been implicated in restenosis after vascular injury, which induces vascular smooth muscle cell (VSMC) migration and proliferation. However, the mechanism for this process is largely unknown. In this study, we report that TP signaling induces VSMC migration and proliferation through activating YAP/TAZ, two major downstream effectors of the Hippo signaling pathway. The TP-specific agonists [1S-[1α,2α(Z),3β(1E,3S*),4 α]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (I-BOP) and 9,11-dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U-46619) induce YAP/TAZ activation in multiple cell lines, including VSMCs. YAP/TAZ activation induced by I-BOP is blocked by knockout of the receptor TP or knockdown of the downstream G proteins Gα12/13 Moreover, Rho inhibition or actin cytoskeleton disruption prevents I-BOP-induced YAP/TAZ activation. Importantly, TP activation promotes DNA synthesis and cell migration in VSMCs in a manner dependent on YAP/TAZ. Taken together, thromboxane A2 signaling activates YAP/TAZ to promote VSMC migration and proliferation, indicating YAP/TAZ as potential therapeutic targets for cardiovascular diseases.

Highlights

Thromboxane A2 (TxA2)4 is produced in many cells/tissues, in platelets (1), and plays an important role in plate
TxA2 exerts its biological activity through its cognate thromboxane A2 receptor (TP) receptor, a G protein-coupled receptor (GPCR) that couples with G␣12/13, G␣q/11, and other trimeric G proteins to regulate downstream effectors (11)
Because YAP/TAZ activity is significantly activated upon TP stimulation in vascular smooth muscle cell (VSMC), we investigated whether YAP/TAZ activation is involved in the proliferation and migration of VSMCs

Summary

Introduction

Thromboxane A2 (TxA2)4 is produced in many cells/tissues, in platelets (1), and plays an important role in plate-. Stimulation of TP Induces YAP/TAZ Dephosphorylation and Nuclear Accumulation—To study TP regulation on YAP/TAZ activity, we treated cells with the TP agonist I-BOP because the physiological TP ligand TxA2 is extremely unstable. The expression of YAP/TAZ target genes, such as CTGF, CYR61, TAGLN, and EDN1, was significantly induced by I-BOP in T/G HA-VSMCs (Fig. 1I).

Results

Conclusion