Paracrine Shear-Stress-Dependent Signaling from Endothelial Cells Affects Downstream Endothelial Function and Inflammation

Cardiovascular diseases (CVDs), mainly ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and major contributors to disability worldwide. Despite their heterogeneity, almost all CVDs share a common feature: the endothelial dysfunction. This is defined as a loss of functionality in terms of anti-inflammatory, anti-thrombotic and vasodilatory abilities of endothelial cells (ECs). Endothelial function is greatly ensured by the mechanotransduction of shear forces, namely, endothelial wall shear stress (WSS). Low WSS is associated with endothelial dysfunction, representing the primary cause of atherosclerotic plaque formation and an important factor in plaque progression and remodeling. In this work, the role of factors released by ECs subjected to different magnitudes of shear stress driving the functionality of downstream endothelium has been evaluated. By means of a microfluidic system, HUVEC monolayers have been subjected to shear stress and the conditioned media collected to be used for the subsequent static culture. The results demonstrate that conditioned media retrieved from low shear stress experimental conditions (LSS-CM) induce the downregulation of endothelial nitric oxide synthase (eNOS) expression while upregulating peripheral blood mononuclear cell (PBMC) adhesion by means of higher levels of adhesion molecules such as E-selectin and ICAM-1. Moreover, LSS-CM demonstrated a significant angiogenic ability comparable to the inflammatory control media (TNFα-CM); thus, it is likely related to tissue suffering. We can therefore suggest that ECs stimulated at low shear stress (LSS) magnitudes are possibly involved in the paracrine induction of peripheral endothelial dysfunction, opening interesting insights into the pathogenetic mechanisms of coronary microvascular dysfunction.

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Plaque-prone hemodynamics impair endothelial function in pig carotid arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00486.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. H2320-H2328 ◽

Cited By ~ 69

Author(s):

Veronica Gambillara ◽

Céline Chambaz ◽

Gabriela Montorzi ◽

Sylvain Roy ◽

Nikos Stergiopulos ◽

...

Keyword(s):

Gene Expression ◽

Nitric Oxide ◽

Endothelial Cells ◽

Shear Stress ◽

Endothelial Dysfunction ◽

Oscillatory Shear ◽

Enos Gene ◽

Low Shear Stress ◽

Oscillatory Shear Stress ◽

Low Shear

Hemodynamic forces play an active role in vascular pathologies, particularly in relation to the localization of atherosclerotic lesions. It has been established that low shear stress combined with cyclic reversal of flow direction (oscillatory shear stress) affects the endothelial cells and may lead to an initiation of plaque development. The aim of the study was to analyze the effect of hemodynamic conditions in arterial segments perfused in vitro in the absence of other stimuli. Left common porcine carotid segments were mounted into an ex vivo arterial support system and perfused for 3 days under unidirectional high and low shear stress (6 ± 3 and 0.3 ± 0.1 dyn/cm2) and oscillatory shear stress (0.3 ± 3 dyn/cm2). Bradykinin-induced vasorelaxation was drastically decreased in arteries exposed to oscillatory shear stress compared with unidirectional shear stress. Impaired nitric oxide-mediated vasodilation was correlated to changes in both endothelial nitric oxide synthase (eNOS) gene expression and activation in response to bradykinin treatment. This study determined the flow-mediated effects on native tissue perfused with physiologically relevant flows and supports the hypothesis that oscillatory shear stress is a determinant factor in early stages of atherosclerosis. Indeed, oscillatory shear stress induces an endothelial dysfunction, whereas unidirectional shear stress preserves the function of endothelial cells. Endothelial dysfunction is directly mediated by a downregulation of eNOS gene expression and activation; consequently, a decrease of nitric oxide production and/or bioavailability occurs.

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Low shear stress damages endothelial function through STAT1 in endothelial cells (ECs)

Journal of Physiology and Biochemistry ◽

10.1007/s13105-020-00729-1 ◽

2020 ◽

Vol 76 (1) ◽

pp. 147-157

Author(s):

Linlin Zhu ◽

Feng Wang ◽

Hongfeng Yang ◽

Junjie Zhang ◽

Shaoliang Chen

Keyword(s):

Endothelial Cells ◽

Shear Stress ◽

Endothelial Function ◽

Low Shear Stress ◽

Low Shear

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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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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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