Role of endothelial permeability hotspots and endothelial mitosis in determining age-related patterns of macromolecule uptake by the rabbit aortic wall near branch points

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Abstract

Background and aims

Transport of macromolecules between plasma and the arterial wall plays a key role in atherogenesis. Scattered hotspots of elevated endothelial permeability to macromolecules occur in the aorta; a fraction of them are associated with dividing cells. Hotspots occur particularly frequently downstream of branch points, where lesions develop in young rabbits and children. However, the pattern of lesions varies with age, and can be explained by similar variation in the pattern of macromolecule uptake. We investigated whether patterns of hotspots and mitosis also change with age.

Methods

Evans’ Blue dye-labeled albumin was injected intravenously into immature or mature rabbits and its subsequent distribution in the aortic wall around intercostal branch ostia examined by confocal microscopy and automated image analysis. Mitosis was detected by immunofluorescence after adding 5-bromo-2-deoxiuridine to drinking water.

Results

Hotspots were most frequent downstream of branches in immature rabbits, but a novel distribution was observed in mature rabbits. Neither pattern was explained by mitosis. Hotspot uptake correlated spatially with the much greater non-hotspot uptake ( p < 0.05), and the same pattern was seen when only the largest hotspots were considered.

Conclusions

The pattern of hotspots changes with age. The data are consistent with there being a continuum of local permeabilities rather than two distinct mechanisms. The distribution of the dye, which binds to elastin and collagen, was similar to that of non-binding tracers and to lesions apart from a paucity at the lateral margins of branches that can be explained by lower levels of fibrous proteins in those regions.

Highlights

•

The pattern of permeability hotspots around aortic branch points changed with age.
•

Non-hotspot, hotspot and large hotspot uptake all showed the same patterns.
•

This is consistent with a continuum of permeabilities rather than two mechanisms.
•

The patterns of hotspots were not explained by patterns of mitosis.
•

The distribution of fibrous proteins influences patterns of Evans’ Blue in the wall.

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Most cited references 42

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Computation in the rabbit aorta of a new metric – the transverse wall shear stress – to quantify the multidirectional character of disturbed blood flow☆

Véronique Peiffer, Spencer J. Sherwin, Peter D. Weinberg (2013)

Spatial variation of the haemodynamic stresses acting on the arterial wall is commonly assumed to explain the focal development of atherosclerosis. Disturbed flow in particular is thought to play a key role. However, widely-used metrics developed to quantify its extent are unable to distinguish between uniaxial and multidirectional flows. We analysed pulsatile flow fields obtained in idealised and anatomically-realistic arterial geometries using computational fluid dynamics techniques, and in particular investigated the multidirectionality of the flow fields, capturing this aspect of near-wall blood flow with a new metric – the transverse wall shear stress (transWSS) – calculated as the time-average of wall shear stress components perpendicular to the mean flow direction. In the idealised branching geometry, multidirectional flow was observed downstream of the branch ostium, a region of flow stagnation, and to the sides of the ostium. The distribution of the transWSS was different from the pattern of traditional haemodynamic metrics and more dependent on the velocity waveform imposed at the branch outlet. In rabbit aortas, transWSS patterns were again different from patterns of traditional metrics. The near-branch pattern varied between intercostal ostia, as is the case for lesion distribution; for some branches there were striking resemblances to the age-dependent patterns of disease seen in rabbit and human aortas. The new metric may lead to improved understanding of atherogenesis.

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Change of Direction in the Biomechanics of Atherosclerosis

Yumnah Mohamied, Ethan M. Rowland, Emma L Bailey … (2014)

The non-uniform distribution of atherosclerosis within the arterial system has been attributed to pro-atherogenic influences of low, oscillatory haemodynamic wall shear stress (WSS) on endothelial cells (EC). This theory is challenged by the changes in lesion location that occur with age in human and rabbit aortas. Furthermore, a number of point-wise comparisons of lesion prevalence and WSS have failed to support it. Here we investigate the hypothesis that multidirectional flow—characterized as the average magnitude of WSS components acting transversely to the mean vector (transWSS)—plays a key role. Maps of lesion prevalence around aortic branch ostia in immature and mature rabbits were compared with equivalent maps of time average WSS, the OSI (an index characterizing oscillatory flow) and transWSS, obtained from computational simulations; Spearman’s rank correlation coefficients were calculated for aggregated data and 95% confidence intervals were obtained by bootstrapping methods. Lesion prevalence correlated positively, strongly and significantly with transWSS at both ages. Correlations of lesion prevalence with the other shear metrics were not significant or were significantly lower than those obtained for transWSS. No correlation supported the low, oscillatory WSS theory. The data are consistent with the view that multidirectional near-wall flow is highly pro-atherogenic. Effects of multidirectional flow on EC, and methods for investigating them, are reviewed. The finding that oscillatory flow has pro-inflammatory effects when acting perpendicularly to the long axis of EC but anti-inflammatory effects when acting parallel to it may explain the stronger correlation of lesion prevalence with transWSS than with the OSI.

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Test of effect of lipid lowering by diet on cardiovascular risk. The Minnesota Coronary Survey.

I Frantz, E Dawson, P Ashman … (2015)

The Minnesota Coronary Survey was a 4.5-year, open enrollment, single end-time double-blind, randomized clinical trial that was conducted in six Minnesota state mental hospitals and one nursing home. It involved 4393 institutionalized men and 4664 institutionalized women. The trial compared the effects of a 39% fat control diet (18% saturated fat, 5% polyunsaturated fat, 16% monounsaturated fat, 446 mg dietary cholesterol per day) with a 38% fat treatment diet (9% saturated fat, 15% polyunsaturated fat, 14% monounsaturated fat, 166 mg dietary cholesterol per day) on serum cholesterol levels and the incidence of myocardial infarctions, sudden deaths, and all-cause mortality. The mean duration of time on the diets was 384 days, with 1568 subjects consuming the diet for over 2 years. The mean serum cholesterol level in the pre-admission period was 207 mg/dl, falling to 175 mg/dl in the treatment group and 203 mg/dl in the control group. For the entire study population, no differences between the treatment and control groups were observed for cardiovascular events, cardiovascular deaths, or total mortality. A favorable trend for all these end-points occurred in some younger age groups.

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Author and article information

Contributors

Peter D. Weinberg

Journal

Journal ID (nlm-ta): Atherosclerosis

Journal ID (iso-abbrev): Atherosclerosis

Title: Atherosclerosis

Publisher: Elsevier

ISSN (Print): 0021-9150

ISSN (Electronic): 1879-1484

Publication date PMC-release: 1 July 2016

Publication date (Print): July 2016

Volume: 250

Pages: 77-83

Affiliations

[a ]Department of Bioengineering, Imperial College London, London, SW7 2AZ, UK

[b ]Department of Aeronautics, Imperial College London, London, SW7 2AZ, UK

Author notes

[∗ ]Corresponding author. Department of Bioengineering, Imperial College London, London, SW7 2AZ, UK.Department of BioengineeringImperial College LondonLondonSW7 2AZUK p.weinberg@ 123456imperial.ac.uk

Article

Publisher ID: S0021-9150(16)30192-7

DOI: 10.1016/j.atherosclerosis.2016.05.017

PMC ID: 4917891

PubMed ID: 27182961

SO-VID: 1fd58261-dc78-486c-bddc-621f5c987df7

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 21 August 2015

Date revision received : 5 February 2016

Date accepted : 6 May 2016

Role of endothelial permeability hotspots and endothelial mitosis in determining age-related patterns of macromolecule uptake by the rabbit aortic wall near branch points

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Abstract

Background and aims

Methods

Results

Conclusions

Highlights

Related collections

Gamma Delta T cells

Most cited references 42

Computation in the rabbit aorta of a new metric – the transverse wall shear stress – to quantify the multidirectional character of disturbed blood flow☆

Change of Direction in the Biomechanics of Atherosclerosis

Test of effect of lipid lowering by diet on cardiovascular risk. The Minnesota Coronary Survey.

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Author notes

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History

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