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

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.

Targeting Early Atherosclerosis: A Focus on Oxidative Stress and Inflammation

“…In the same line, Wang et al observed that YAP/TAZ activation via biomechanical stretching regulates critical aspects of the human umbilical arterial smooth muscle cell (HUASMC) phenotypic switch, as YAP/TAZ knockdown attenuated the stretch-induced proliferative and proinflammatory phenotypes. Moreover, they reported that treatment with atorvastatin suppressed YAP/TAZ expression [42].…”

The protective effect of dronedarone on the structure and mechanical properties of the aorta in hypertensive rats by decreasing the concentration of symmetric dimethylarginine (SDMA)

“…When compared to these studies, dronedarone did not show any differential effects on aortic remodeling (decreased aortic media layer and CSA); however, dronedarone also produced changes in the passive mechanical properties of the aorta. Increases in wall stress and biomechanical stretch are a consequence of hypertension and are potent drivers of arterial remodeling [35]. These alterations are also linked to a higher risk of adverse cardiovascular events.…”

Mechanical Regulation of Protein Translation in the Cardiovascular System

“…Pathological mechanical trauma and changes to cyclic stretch triggers VSMCs to undergo gene, protein expression and phenotypic changes. Examples of this are decreases in contractile genes such as SM22α and those encoding myosin light chain, and increases in cell hypertrophy, proliferation and migration (Huang et al, 1999;Feil et al, 2004;Chiu et al, 2013;Wang et al, 2018). The dysregulated proliferative VSMC phenotype is associated with cardiovascular states where the mechanical environment is perturbed such as pulmonary hypertension and atherosclerosis (Morrell et al, 2009;Bennett et al, 2016).…”