Elevated Uptake of Plasma Macromolecules by Regions of Arterial Wall Predisposed to Plaque Instability in a Mouse Model
Author(s)
Type
Journal Article
Abstract
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.
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.
Date Issued
2014-12-22
Date Acceptance
2014-11-28
Citation
PLoS One, 2014, 9 (12)
ISSN
1932-6203
Publisher
PUBLIC LIBRARY SCIENCE
Journal / Book Title
PLoS One
Volume
9
Issue
12
Copyright Statement
© 2014 Mohri et al. This is an openaccess
article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction
in any medium, provided the original author
and source are credited.
article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction
in any medium, provided the original author
and source are credited.
License URL
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
RABBIT AORTIC-WALL
LOW-DENSITY-LIPOPROTEIN
TERM ALBUMIN UPTAKE
SHEAR-STRESS
ENDOTHELIAL PERMEABILITY
NITRIC-OXIDE
ATHEROSCLEROTIC LESIONS
IN-VIVO
MICE
PATTERNS
Publication Status
Published
Article Number
e115728