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