Restoring vascular endothelial autophagic flux reduces atherosclerotic lesions

Atherosclerotic lesions preferentially develop in arterial areas exposed to low shear stress, where endothelial cells express a pro-inflammatory, apoptotic, and senescent phenotype. Autophagy is a lysosomal mechanism that recycles damaged organelles and protein aggregates to maintain cellular homeostasis. Stimulation of autophagy in high shear stress conditions is an atheroprotective process. Conversely, endothelial cells exposed to atheroprone low shear stress present a defective autophagic flux, which favors a pro-inflammatory phenotype and the formation of atherosclerotic lesions. Since an efficient autophagic flux is dependent on α-tubulin acetylation, which is reduced under low shear stress, we hypothesized that increasing α-tubulin acetylation could restore adequate levels of autophagy in endothelial cells exposed to low shear stress. We found that blocking Histone Deacetylase 6 (HDAC6) activity, either by pharmacological inhibition (Tubastatin-A) or genetic approaches (shHDAC6), raised levels of acetylated α-tubulin, as well as LC3-II/I ratio, LC3 punctae area and autophagic flux in cultured endothelial cells exposed to low shear stress. This effect was associated with a reduced expression of inflammatory markers (Intercellular adhesion molecule-1 (ICAM-1), Vascular cell Adhesion Protein-1 (VCAM-1) and Monocyte Chemoattractant Protein-1 (MCP-1)) in Tumor Necrosis Factor-alpha (TNF-α)-stimulated cells. We observed increased endothelial autophagic flux in the aortic arch of the HDAC6-/-/ApoE-/- mice. Subsequently, atherosclerotic plaque size was significantly reduced in the atheroprone areas of chimeric HDAC6-/-/ApoE-/- mice, transplanted with HDAC6+/+/ApoE-/- bone marrow, when compared to HDAC6+/+/ApoE-/- littermate controls. Taken together, these results indicate that targeting α-tubulin acetylation, via HDAC6-inhibition, may be an interesting strategy to restore endothelial autophagic flux and to promote an atheroprotective endothelial phenotype despite unfavorable shear stress conditions.

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Restoration of endothelial autophagic flux in vascular endothelial cells exposed to low shear stress reduces atherosclerotic lesions

Archives of Cardiovascular Diseases Supplements ◽

10.1016/j.acvdsp.2021.04.078 ◽

2021 ◽

Vol 13 (2) ◽

pp. 177

Author(s):

S. Chatterjee ◽

M. Kheloufi ◽

S. Mazlan ◽

X. Loyer ◽

T. Mckinsey ◽

...

Keyword(s):

Endothelial Cells ◽

Shear Stress ◽

Vascular Endothelial Cells ◽

Autophagic Flux ◽

Vascular Endothelial ◽

Atherosclerotic Lesions ◽

Low Shear Stress ◽

Low Shear

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Restoration of endothelial autophagic flux in vascular endothelial cells exposed to low shear stress

Archives of Cardiovascular Diseases Supplements ◽

10.1016/j.acvdsp.2019.02.009 ◽

2019 ◽

Vol 11 (2) ◽

pp. 185

Author(s):

S. Chatterjee ◽

M. Kheloufi ◽

P.M. Coly ◽

C. Boulanger

Keyword(s):

Endothelial Cells ◽

Shear Stress ◽

Vascular Endothelial Cells ◽

Autophagic Flux ◽

Vascular Endothelial ◽

Low Shear Stress ◽

Low Shear

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Endothelial Cell Morphometry of Atherosclerotic Lesions and Flow Profiles at Aortic Bifurcations in Cholesterol Fed Rabbits

Journal of Biomechanical Engineering ◽

10.1115/1.2891387 ◽

1992 ◽

Vol 114 (3) ◽

pp. 301-308 ◽

Cited By ~ 28

Author(s):

Mitsuji Okano ◽

Yoji Yoshida

Keyword(s):

Endothelial Cells ◽

Shear Stress ◽

Lipid Deposition ◽

High Shear ◽

High Shear Stress ◽

Atherosclerotic Lesions ◽

Flow Profiles ◽

Flow Divider ◽

Low Shear Stress ◽

Low Shear

Observations on shapes of endothelial cells both in sudanophilic and nonsudanophilic regions at bifurcations of the brachiocephalic (BC) and left subclavian (SA) arteries in hyperlipidemic rabbits were performed under a SEM. The stagnation point of flow and leading edges of flow dividers were nonsudanophilic and covered by round and long fusiform endothelial cells, respectively. The hips of flow dividers of both branchings, proven to be relatively low shear stress regions, by movement of microspheres in steady flow, were sudanophilic and covered by ellipsoidal cells. Similar studies were carried out in normolipidemic rabbits. It might be concluded that lipid deposition in hyperlipidemic rabbits occurs in relatively low shear stress regions, where endothelial cells are functionally activated, rather than in laminar high shear stress regions at the flow divider.

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CXCR4 expression in atherosclerotic lesions induced by low shear stress

Cell Biology International ◽

10.1016/j.cellbi.2008.01.085 ◽

2008 ◽

Vol 32 (3) ◽

pp. S18-S19

Author(s):

Dang Heng Wei ◽

Gui Xue Wang ◽

Yi Ping Xia ◽

Jian Jun Lei ◽

Lu Shang Liu ◽

...

Keyword(s):

Shear Stress ◽

Cxcr4 Expression ◽

Atherosclerotic Lesions ◽

Low Shear Stress ◽

Low Shear

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Effects of Caveolin-1-ERK1/2 pathway on endothelial cells and smooth muscle cells under shear stress

Experimental Biology and Medicine ◽

10.1177/1535370219892574 ◽

2019 ◽

Vol 245 (1) ◽

pp. 21-33 ◽

Cited By ~ 1

Author(s):

Lan Jia ◽

Lihua Wang ◽

Fang Wei ◽

Chen Li ◽

Zhe Wang ◽

...

Keyword(s):

Endothelial Cells ◽

Shear Stress ◽

Smooth Muscle ◽

Growth Factor ◽

Caveolin 1 ◽

Low Shear Stress ◽

And Migration ◽

Oscillating Shear Stress ◽

Low Shear ◽

Proliferation And Migration

Hemodynamic forces have an important role in venous intimal hyperplasia, which is the main cause of arteriovenous fistula dysfunction. Endothelial cells (ECs) constantly exposed to the shear stress of blood flow, converted the mechanical stimuli into intracellular signals, and interacted with the underlying vascular smooth muscle cells (VSMCs). Caveolin-1 is one of the important mechanoreceptors on cytomembrane, which is related to vascular abnormalities. Extracellular signal-regulated kinase1/2 (ERK1/2) pathway is involved in the process of VSMCs proliferation and migration. In the present study, we explore the effects of Caveolin-1-ERK1/2 pathway and uremia toxins on the endothelial cells and VSMCs following shear stress application. Different shear stress was simulated with a ECs/VSMCs cocultured parallel-plate flow chamber system. Low shear stress and oscillating shear stress up-regulated the expression of fibroblast growth factor-4, platelet-derived growth factor-BB, vascular endothelial growth factor-A, ERK1/2 phosphorylation in endothelial cells, and proliferation and migration of VSMCs but down-regulated the Caveolin-1 expression in endothelial cells. Uremia toxin induces the proliferation and migration of VSMCs but not in a Caveolin-1-dependent manner in the static environment. Low shear stress-induced proliferation and migration of VSMCs is inhibited by Caveolin-1 overexpression and ERK1/2 suppression. Shear stress-regulated VSMC proliferation and migration is an endothelial cells-dependent process. Low shear stress and oscillating shear stress exert atherosclerotic influences on endothelial cells and VSMCs. Low shear stress modulated proliferation and migration of VSMCs through Caveolin-1-ERK1/2 pathway, which suggested that Caveolin-1 and ERK1/2 can be used as a new therapeutic target for the treatment of arteriovenous fistula dysfunction. Impact statement Venous intimal hyperplasia is the leading cause of arteriovenous fistula (AVF) dysfunction. This article reports that shear stress-regulated vascular smooth muscle cells (VSMCs) proliferation and migration is an endothelial cell (EC)-dependent process. Low shear stress (LSS) and oscillating shear stress (OSS) exert atherosclerotic influences on the ECs and VSMCs. LSS-induced proliferation and migration of VSMCs is inhibited by Caveolin-1 overexpression and extracellular signal-regulated kinase1/2 (ERK1/2) suppression, which suggested that Caveolin-1 and ERK1/2 can be used as a new therapeutic target for the treatment of AVF dysfunction.

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Low Shear Stress Upregulates CX3CR1 Expression by Inducing VCAM-1 via the NF-κB Pathway in Vascular Endothelial Cells

Cell Biochemistry and Biophysics ◽

10.1007/s12013-020-00931-4 ◽

2020 ◽

Vol 78 (3) ◽

pp. 383-389 ◽

Cited By ~ 1

Author(s):

Yiwei Zhao ◽

Peile Ren ◽

Qiufang Li ◽

Shafiu Adam Umar ◽

Tan Yang ◽

...

Keyword(s):

Endothelial Cells ◽

Shear Stress ◽

Protein Expression ◽

Vascular Endothelial Cells ◽

Critical Role ◽

Mrna Levels ◽

Vascular Endothelial ◽

Low Shear Stress ◽

Low Shear ◽

Cx3cr1 Expression

Abstract Atherosclerosis is a significant cause of mortality and morbidity. Studies suggest that the chemokine receptor CX3CR1 plays a critical role in atherogenesis. Shear stress is an important mechanical force that affects blood vessel function. In this study, we investigated the effect of shear stress on CX3CR1 expression in vascular endothelial cells (VECs). First, cells were exposed to different shear stress and then CX3CR1 mRNA and protein were measured by quantitative RT-PCR and western blot analysis, respectively. CX3CR1 gene silencing was used to analyze the molecular mechanisms underlying shear stress-mediated effects on CX3CR1 expression. CX3CR1 mRNA and protein expression were significantly increased with 4.14 dyne/cm2 of shear stress compared with other tested levels of shear stress. We observed a significant increase in CX3CR1 mRNA levels at 2 h and CX3CR1 protein expression at 4 h. CX3CR1-induced VCAM-1 expression in response to low shear stress by activating NF-κB signaling pathway in VECs. Our findings demonstrate that low shear stress increases CX3CR1 expression, which increases VCAM-1 expression due to elevated NF-κB activation. The current study provides evidence of the correlation between shear stress and atherosclerosis mediated by CX3CR1.

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