Atherosclerotic plaques are focal accumulations of lipids, fibrous proteins and inflammatory cells in the intima and inner media of the arterial wall and therefore cannot be explained entirely by systemic risk factors (e.g. elevated blood pressure, plasma cholesterol, etc.). Variation in the accumulation of plasma macromolecules within the inner wall may be one localising factor but the basic transport mechanisms involved in such accumulation are incompletely understood.
Transmural water transport, driven by pressure gradients, plays a major role in the transport of the largest macromolecules (eg: lipoproteins): they are predominantly transported by advection. Studying the factors affecting the hydraulic conductance (Lp) of the arterial wall is therefore the first step in discovering the transport routes of large molecules within the arterial wall and has an impact on both our understanding of the mechanisms behind the lipid accumulation that characterises atherosclerosis and on the design of drugs of similar molecular size targeted at the arterial wall.
One such factor is the role of smooth muscle cell tone. We have developed an ex vivo preparation of the rat aortic bifurcation in which it is excised and placed in a bath of physiological buffer while its lumen is maintained at a steady pressure of 100mmHg; it is then treated with increasing concentrations of noradrenaline. By measuring hydraulic flux we can calculate Lp, averaged over the whole vessel, and can determine the effects of muscle contraction on it. Additionally, we place a fluorescent protein tracer, rhodamine-albumin, in the luminal space. It is transported through the wall and can be measured in the abluminal bath. Allowing this tracer’s transport to reach a steady state before formaldehyde fixation and 3D confocal microscopy gives us a realistic structure of the available space for mobile water in the vessel wall, with which we can perform numerical simulations of water transport.
Lp was found to be significantly lower at noradrenaline concentrations ≥100 nM than in controls. This threshold concentration corresponds to previously reported findings on the tension-concentration relationship of isolated rabbit aortic strips.1 We are currently performing numerical simulations on small regions within the media to determine the permeability of the structure as it changes with noradrenaline concentration. This will give us an estimate of the Lp of the media alone and, by subtraction, the Lp of the endothelium.
Funding BHF, BHF Centre of Research Excellence and EU.
Furchgott RF, Bhadrakom S. J Pharmacol Exp Ther. 1953; 108(2):129–43
- Hydraulic Conductance
- Mass Transport
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