Spatial Regulation of Inflammation by Human Aortic Endothelial Cells in a Linear Gradient of Shear Stress

Tsou, J.K.; Gower, R. Michael; Ting, Harold J.; Schaff, Ulrich Y.; Insana, Michael F.; Passerini, Anthony G.; Simon, Scott I.

doi:10.1080/10739680701724359

Cited by 77 publications

(93 citation statements)

References 47 publications

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“…Ivabradine induced protection from inflammation in the aorta (exposed to flow) but did not alter the inflammatory state of EC in conditions where flow was unaltered (either in vitro or in vivo), providing strong evidence that ivabradine functions indirectly via alteration of vascular mechanics. This is consistent with in vitro studies showing that VCAM-1 expression correlates inversely with shear stress magnitude 31 .…”

Section: Discussionsupporting

confidence: 80%

Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

Luong¹,

Duckles²,

Schenkel³

et al. 2016

Thromb Haemost

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"Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries", Thrombosis and Haemostasis, 2016: 116/1 (July) pp. [181][182][183][184][185][186][187][188][189][190]., is available online at: https://doi.org/10.1160/TH16-03-0214.eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ Reuse Unless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version -refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher's website. TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. 2 SUMMARY AimsBlood flow generates wall shear stress (WSS) which alters endothelial cell (EC) function. Low WSS promotes vascular inflammation and atherosclerosis whereas high uniform WSS is protective. Ivabradine decreases heart rate leading to altered hemodynamics. Besides its cardio-protective effects, ivabradine protects arteries from inflammation and atherosclerosis via unknown mechanisms. We hypothesised that ivabradine protects arteries by increasing WSS to reduce vascular inflammation. Methods and ResultsHypercholesterolemic mice were treated with ivabradine for 7 weeks in drinking water or remained untreated as a control. En face immunostaining demonstrated that treatment with ivabradine reduced the expression of pro-inflammatory VCAM-1 (p<0.01) and enhanced the expression of anti-inflammatory eNOS (p<0.01) at the inner curvature of the aorta. We concluded that ivabradine alters EC physiology indirectly via modulation of flow because treatment with ivabradine had no effect in ligated carotid arteries in vivo, and did not influence the basal or TNF -induced expression of inflammatory (VCAM-1, MCP-1) or protective (eNOS, HMOX1, KLF2, KLF4) genes in cultured EC. We therefore considered whether ivabradine can alter WSS which is a regulator of EC inflammatory activation. Computational fluid dynamics demonstrated that ivabradine treatment reduced heart rate by 20% and enhanced WSS in the aorta. ConclusionsIvabradine treatment altered hemodynamics in the murine aorta by increasing the magnitude of shear stress. This was accompanied by induction of eNOS and suppression of VCAM-1, whereas ivabradine did not alter EC that could not respond to flow. Thus ivabradine protects arteries by altering local mechanical conditions to trigger an anti-inflammatory response.

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Section: Discussionsupporting

confidence: 80%

Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

Luong¹,

Duckles²,

Schenkel³

et al. 2016

Thromb Haemost

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“…In vitro studies have confirmed the ability of ECs to alter their phenotype in response to fluid shear stress into a pro-inflammatory or proatherogenic phenotype (10,11). The recruitment and attachment of leukocyte to the endothelium is dependent on the cell phenotype and the local fluid forces acting on the circulating leukocyte (12,13). The local response of the endothelial cells and the complex hemodynamics created by the geometry of a stenosis likely plays a role in the regional attachment of leukocytes.…”

Section: Introductionmentioning

confidence: 91%

Neutrophil Adhesion on Endothelial Cells in a Novel Asymmetric Stenosis Model: Effect of Wall Shear Stress Gradients

et al. 2010

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Leukocytes play a pivotal role in the progression of atherosclerosis. A novel three dimensional in vitro asymmetric stenosis model was used to better investigate the role of local hemodynamics in the adhesion of leukocytes to an established plaque. The adhesion of a human promyelocytic cell line (NB4) on a human abdominal aortic endothelial cell (EC) monolayer was quantified. NB4 cells were circulated over TNF-α stimulated and non-stimulated ECs for 1 or 6 hrs at 1.25 or 6.25 dynes/cm 2 and compared to static conditions. Cytokine stimulation increased significantly endothelial cell expression of intercellular adhesion molecule and vascular cell adhesion molecule. Under static conditions, neutrophils adhered overall more than under flow, with decreased adhesion with increasing shear. Adhesion was significantly higher in the recirculation region distal to the stenosis than in the inlet. Preshearing the endothelial cells decreased the expression of cell adhesion molecules in inflamed endothelium and significantly decreased adhesion. However, the ratio of adhesion between the recirculation zone and the inlet increased, hence exhibiting an increased regional difference. This work suggests an important role for neutrophil-endothelial cell interactions in the atherosclerotic process, especially in wall shear gradient regions. This is important clinically, potentially helping to explain plaque stability.

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“…Figure 11. Receptor surface density versus WSS relationship determined by curve fitting to in vitro data for TNF-a stimulated CAM expression, obtained from [51]. Here, stars, squares and circles denote experimental data for ICAM-1, VCAM-1 and E-selectin, respectively, and the solid lines represent the corresponding fitted data.…”

Section: Resultsmentioning

confidence: 99%

“…These CAMs, in particular VCAM-1, are regarded as early markers of atherosclerosis due to their upregulation at the site of inflammation. First, a phenomenological model (see appendix A) correlating CAM expression to local WSS as detailed in [16,44,51] was used to estimate the surface density of the target receptor with respect to their unstimulated expression under static conditions (see electronic supplementary material, figure S6). Spherical NPs (d p ¼ 100 nm) uniformly coated with anti-VCAM-1 antibodies (aVCAM-1 NPs) were then introduced into the bloodstream by placing a bolus of NPs at the SFA inlet as before.…”

Section: Predicting the Vascular Deposition Of Nanoparticles In The Smentioning

confidence: 99%

Magnetic resonance imaging-based computational modelling of blood flow and nanomedicine deposition in patients with peripheral arterial disease

Hossain

Zhang

et al. 2015

J. R. Soc. Interface.

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Peripheral arterial disease (PAD) is generally attributed to the progressive vascular accumulation of lipoproteins and circulating monocytes in the vessel walls leading to the formation of atherosclerotic plaques. This is known to be regulated by the local vascular geometry, haemodynamics and biophysical conditions. Here, an isogeometric analysis framework is proposed to analyse the blood flow and vascular deposition of circulating nanoparticles (NPs) into the superficial femoral artery (SFA) of a PAD patient. The local geometry of the blood vessel and the haemodynamic conditions are derived from magnetic resonance imaging (MRI), performed at baseline and at 24 months post intervention. A dramatic improvement in blood flow dynamics is observed post intervention. A 500% increase in peak flow rate is measured in vivo as a consequence of luminal enlargement. Furthermore, blood flow simulations reveal a 32% drop in the mean oscillatory shear index, indicating reduced disturbed flow post intervention. The same patient information (vascular geometry and blood flow) is used to predict in silico in a simulation of the vascular deposition of systemically injected nanomedicines. NPs, targeted to inflammatory vascular molecules including VCAM-1, E-selectin and ICAM-1, are predicted to preferentially accumulate near the stenosis in the baseline configuration, with VCAM-1 providing the highest accumulation (approx. 1.33 and 1.50 times higher concentration than that of ICAM-1 and E-selectin, respectively). Such selective deposition of NPs within the stenosis could be effectively used for the detection and treatment of plaques forming in the SFA. The presented MRI-based computational protocol can be used to analyse data from clinical trials to explore possible correlations between haemodynamics and disease progression in PAD patients, and potentially predict disease occurrence as well as the outcome of an intervention.

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Spatial Regulation of Inflammation by Human Aortic Endothelial Cells in a Linear Gradient of Shear Stress

Cited by 77 publications

References 47 publications

Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

Neutrophil Adhesion on Endothelial Cells in a Novel Asymmetric Stenosis Model: Effect of Wall Shear Stress Gradients

Magnetic resonance imaging-based computational modelling of blood flow and nanomedicine deposition in patients with peripheral arterial disease

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