Shear Stress Induces Phenotypic Modulation of Vascular Smooth Muscle Cells via AMPK/mTOR/ULK1-Mediated Autophagy

Abstract

Phenotypic modulation of vascular smooth muscle cells (VSMCs) is involved in the pathophysiological processes of the intracranial aneurysms (IAs). Although shear stress has been implicated in the proliferation, migration, and phenotypic conversion of VSMCs, the molecular mechanisms underlying these events are currently unknown. In this study, we investigated whether shear stress(SS)-induced VSMC phenotypic modulation was mediated by autophagy involved in adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) pathway. The results show that shear stress could inhibit the expression of key VSMC contractile genes and induce pro-inflammatory/matrix-remodeling genes levels, contributing to VSMCs phenotypic switching from a contractile to a synthetic phenotype. More importantly, Shear stress also markedly increased the levels of the autophagy marker microtubule-associated protein light chain 3-II (LC3II), Beclin-1, and p62 degradation. The autophagy inhibitor 3-methyladenine (3-MA) significantly blocked shear-induced phenotypic modulation of VSMCs. To further explore the molecular mechanism involved in shear-induced autophagy, we found that shear stress could activate AMPK/mTOR/ULK1 signaling pathway in VSMCs. Compound C, a pharmacological inhibitor of AMPK, significantly reduced the levels of p-AMPK and p-ULK, enhanced p-mTOR level, and finally decreased LC3II and Beclin-1 level, which suggested that activated AMPK/mTOR/ULK1 signaling was related to shear-mediated autophagy. These results indicate that shear stress promotes VSMC phenotypic modulation through the induction of autophagy involved in activating the AMPK/mTOR/ULK1 pathway.

Chicoric acid prevents PDGF-BB-induced VSMC dedifferentiation, proliferation and migration by suppressing ROS/NFκB/mTOR/P70S6K signaling cascade

“…Activation of mTOR/P70S6K is responsible for VSMC dedifferentiation and proliferation [52] . Shear stress activates mTOR signaling to induce phenotypic modulation of VSMCs [53] . Exogenous miR-761 delivery inhibits angiotensin II-induced VSMC proliferation by targeting mTOR [54] .…”

Inflammatory Smooth Muscle Cells Induce Endothelial Cell Alterations to Influence Cerebral Aneurysm Progression via Regulation of Integrin and VEGF Expression

“…Dynamic changes and eventual loss of the media layer contribute to aneurysm formation and rupture. Previous histological studies have demonstrated that normally contractile SMCs respond to environmental cues by undergoing phenotypic changes, causing them to manifest a pro-inflammatory, pro-remodeling, and dedifferentiated phenotype 5 –8 . The pro-inflammatory phenotype is characterized by reduced levels of the contractile elements of SMCs, accompanied by increased levels of transcription factors involved in promoting inflammation, recruitment of reactive oxygen species, and matrix remodeling 9 –11 .…”

Androgens deficiency impairs thoracic aortic vascular function by promoting smooth muscle cell proliferation via an autophagy dependent manner

“…In response to endothelial cell dysfunction, VSMCs, the main components of the arterial vessel wall, undergo a phenotypic switch from a contractile phenotype to a synthetic phenotype that is essential for vascular remodeling 25 . This VSMC phenotypic modulation is regulated by autophagy, and a previous study reported that the expression of the autophagy marker Beclin 1 is increased in shear stress-induced VSMC phenotypic modulation 26 . Autophagy plays an essential role in maintaining cellular homeostasis in physiological conditions 27,28 and participates in various physiological cellular processes as well as some pathological processes.…”