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Cell Physiol Biochem. 2018;51(2):842-853. doi: 10.1159/000495376. Epub 2018 Nov 22.

Arterial Wall Stress Induces Phenotypic Switching of Arterial Smooth Muscle Cells in Vascular Remodeling by Activating the YAP/TAZ Signaling Pathway.

Wang Y1,2,3, Cao W1,2, Cui J1,2, Yu Y1,2, Zhao Y4, Shi J5, Wu J1,2, Xia Z6, Yu B1,2, Liu J7,8,9.

Author information

1
Cardiology Department, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
2
Key Laboratories of the Education Ministry for Myocardial Ischemia Mechanisms and Treatment, Harbin, China.
3
Department of Biomedical Science, University of Hong Kong, Hong Kong, China.
4
Department of Vascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
5
Department of Cardiology, Eighth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
6
Department of Anesthesiology, University of Hong Kong, Hong Kong, China.
7
Cardiology Department, Second Affiliated Hospital of Harbin Medical University, Harbin, Chinajingjinl@hku.hk.
8
Key Laboratories of the Education Ministry for Myocardial Ischemia Mechanisms and Treatment, Harbin, Chinajingjinl@hku.hk.
9
Department of Anesthesiology, University of Hong Kong, Hong Kong, Chinajingjinl@hku.hk.

Abstract

BACKGROUND/AIMS:

Increasing wall stress or biomechanical stretch experienced by arteries influences the initiation of atherosclerotic lesions. This initiation is mediated by Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which are both effectors of the Hippo pathway. In this study, the functional roles of YAP/TAZ proteins in the regulation of the stretch-mediated programing of human umbilical arterial smooth muscle cells (HUASMCs) to a proliferative phenotype were examined.

METHODS:

HUASMCs were seeded on a Matrigel-coated silicone chamber and subjected to biomechanical stretch for 24 h after 48 h of growth. YAP/TAZ small interfering RNA was used to specifically knockdown YAP/ TAZ expression in HUASMCs.

RESULTS:

We observed that YAP/TAZ activation via biomechanical stretching is involved in the regulation of critical aspects of the HUASMC phenotypic switch. YAP/TAZ knockdown significantly attenuated the stretch-induced proliferative and pro-inflammatory phenotypes in HUASMCs. Furthermore, treatment with atorvastatin, an anti-atherosclerotic drug, attenuated the stretch-induced phenotypic switch of HUASMCs from the contractile to synthetic state by suppressing YAP/TAZ expression. Additional investigations demonstrated the role of stretch in inhibiting the Hippo pathway, leading to the activation of PI3-kinase (PI3K) and phosphoinositide dependent kinase (PDK1); the key molecule for the regulation of the PDK1 and Hippo complex interaction was Sav1. These results showed the importance of YAP/TAZ activation, induced by biomechanical stretch, in promoting atheroprone phenotypes in HUASMCs.

CONCLUSION:

Taken together, our findings revealed a mechanism by which YAP/TAZ activation contributes to the pathogenesis of atherosclerosis.

KEYWORDS:

Arterial Smooth Muscle Cells; Cyclic Strain; Shear Stress; Vascular Remodeling; YAP/TAZ

PMID:
30466081
DOI:
10.1159/000495376
[Indexed for MEDLINE]
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