Strain-Dependent Differences in the Pattern of Aortic Lipid Deposition in Cholesterol-Fed Rabbits

Barnes, S.; Weinberg, Peter D.

doi:10.1006/exmp.2001.2395

Cited by 15 publications

(20 citation statements)

References 33 publications

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“…Transport routes for macromolecules are size dependent and, if inferences can be made from studies in the microcirculation [36] , not all albumin transport will take place via the route used by large lipoproteins. Despite this, studies in the aorta show good agreement between uptake patterns for albumin [9] , [10] and low density lipoprotein [37] (the latter being transported by pathways independent of the LDL receptor [38] ); and, as here, patterns of albumin uptake show an excellent spatial correlation with patterns of early lesion development [13] – [15] .…”

Section: Discussionmentioning

confidence: 92%

“…Uptake of circulating macromolecules by the aortic wall of the mature rabbit is highly non-uniform [9] , [10] ; its pattern depends on blood flow [11] and NO synthesis [12] , [13] , and correlates spatially with the subsequent occurrence of spontaneous [14] and diet-induced [13] , [15] lipid deposition. Here we test the hypothesis that, prior to the development of lesions in the cuffed mouse carotid, macromolecule uptake is elevated in both regions prone to lesion development, is sensitive to flow and NO synthesis, and is higher upstream than downstream of the cuff, thereby providing a plausible mechanism for why the upstream rather than the downstream lesions most closely resemble the TCFA.…”

Section: Introductionmentioning

confidence: 99%

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Elevated Uptake of Plasma Macromolecules by Regions of Arterial Wall Predisposed to Plaque Instability in a Mouse Model

et al. 2014

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Atherosclerosis may be triggered by an elevated net transport of lipid-carrying macromolecules from plasma into the arterial wall. We hypothesised that whether lesions are of the thin-cap fibroatheroma (TCFA) type or are less fatty and more fibrous depends on the degree of elevation of transport, with greater uptake leading to the former. We further hypothesised that the degree of elevation can depend on haemodynamic wall shear stress characteristics and nitric oxide synthesis. Placing a tapered cuff around the carotid artery of apolipoprotein E -/- mice modifies patterns of shear stress and eNOS expression, and triggers lesion development at the upstream and downstream cuff margins; upstream but not downstream lesions resemble the TCFA. We measured wall uptake of a macromolecular tracer in the carotid artery of C57bl/6 mice after cuff placement. Uptake was elevated in the regions that develop lesions in hyperlipidaemic mice and was significantly more elevated where plaques of the TCFA type develop. Computational simulations and effects of reversing the cuff orientation indicated a role for solid as well as fluid mechanical stresses. Inhibiting NO synthesis abolished the difference in uptake between the upstream and downstream sites. The data support the hypothesis that excessively elevated wall uptake of plasma macromolecules initiates the development of the TCFA, suggest that such uptake can result from solid and fluid mechanical stresses, and are consistent with a role for NO synthesis. Modification of wall transport properties might form the basis of novel methods for reducing plaque rupture.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Elevated Uptake of Plasma Macromolecules by Regions of Arterial Wall Predisposed to Plaque Instability in a Mouse Model

et al. 2014

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“…More complex analyses can also be performed. Thus, in one earlier study (Barnes and Weinberg 2001), spreadsheet data were used to calculate the centre of gravity of lesions as an index of their location, and hence to reveal subtle but statistically significant effects of rabbit strain on lesion distribution. Analyses can be automated using the Excel macro programming language.…”

Section: Discussionmentioning

confidence: 99%

Use of a desktop scanner and spreadsheet software for mapping arterial disease

Cremers

Weinberg

2006

Scanning

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Summary:Mapping the surface area and distribution of atherosclerosis has so far required photographic, video, or photomicrographic imaging of the inner surface of the arterial wall, as well as laborious manual or sophisticated image processing methods of quantification. We investigated whether comparable results could be obtained by using a conventional flatbed scanner and readily available spreadsheet software. Lipid-rich lesions near 21 aortic branches from cholesterol-fed rabbits were mapped using a scanner-based technique and an established photomicrographic technique. When the tissue was counterstained and held on the scanner by a transparent weight to obtain adequate contrast and prevent detection of adventitial staining, the areas of lipid deposition detected by the two methods correlated highly (R 2 =0.99). Discrepancies arose mainly at the edges of lesions, probably because of alignment errors and better flattening of the tissue on the scanner; when these were accounted for, discrepancies occurred in <1% of the total area examined. The new method produces results comparable with previous procedures, but is much more rapid and requires only office equipment and software.

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“…The initial experiments addressing this problem gave confusing results, some mature rabbits developing the downstream pattern and others the more upstream pattern. This was at first attributed to minor differences in diet [80]but subsequent studies [81, 82]have shown that it is in fact explained by an effect of rabbit strain: the strain of rabbit determines the age at which arterial transport properties switch from the immature to the mature pattern [82]. Although some strains switch patterns at around 6 months of age, others do so substantially later.…”

Section: A New Animal Modelmentioning

confidence: 99%

Rate-Limiting Steps in the Development of Atherosclerosis: The Response-to-Influx Theory

Weinberg

2004

J Vasc Res

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A large number of processes are involved in the pathogenesis of atherosclerosis but it is unclear which of them play a rate-limiting role. One way of resolving this problem is to investigate the highly non-uniform distribution of disease within the arterial system; critical steps in lesion development should be revealed by identifying arterial properties that differ between susceptible and protected sites. Although the localisation of atherosclerotic lesions has been investigated intensively over much of the 20th century, this review argues that the factor determining the distribution of human disease has only recently been identified. Recognition that the distribution changes with age has, for the first time, allowed it to be explained by variation in transport properties of the arterial wall; hitherto, this view could only be applied to experimental atherosclerosis in animals. The newly discovered transport variations which appear to play a critical role in the development of adult disease have underlying mechanisms that differ from those elucidated for the transport variations relevant to experimental atherosclerosis: they depend on endogenous NO synthesis and on blood flow. Manipulation of transport properties might have therapeutic potential.

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Strain-Dependent Differences in the Pattern of Aortic Lipid Deposition in Cholesterol-Fed Rabbits

Cited by 15 publications

References 33 publications

Elevated Uptake of Plasma Macromolecules by Regions of Arterial Wall Predisposed to Plaque Instability in a Mouse Model

Elevated Uptake of Plasma Macromolecules by Regions of Arterial Wall Predisposed to Plaque Instability in a Mouse Model

Use of a desktop scanner and spreadsheet software for mapping arterial disease

Rate-Limiting Steps in the Development of Atherosclerosis: The Response-to-Influx Theory

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