(596y) Vessel Wall Transport: Can Increasing the Concentration of the Membrane Protein Aquaporin-1 Slow Down Pre-Lesion Atherosclerosis?

Macromolecular (read: low-density lipoprotein cholesterol or LDL) transport across the vessel wall appears to be the earliest pre-atherosclerotic event. It is known to occur due to advection: Transmural (i.e., across the vessel wall) pressure differences (i.e., blood pressure) drive plasma (water and small solutes) across the monolayer of endothelial cells (EC) that line the inside of the vessel wall. One EC every few thousand has junctions that are temporarily widened, some because they are either dying or dividing, and the transmural flow can advect large tracers through them into the wall. A wall parameter, the hydraulic conductivity (L_p), defined as the ratio of the transmural water flux to hydrostatic pressure difference, is central to the understanding of this transmural water transport. On one hand, it advects macromolecules like LDL into the arterial subendothelial intima (SI) through these rare, widened EC leaks and spreads it there, thereby giving it the chance to bind to extracellular matrix (ECM) in the SI layer and possibly to trigger the start of atherosclerotic lesion formation. On the other hand, the overall water flow across the normal (non-leaky) endothelium dilutes the lo­cal SI LDL concentration, thereby likely slow­ing binding kine­tics, and washing not-yet-bound lipid further into the wall. Our group’s discovery of the presence of the ubiquitous water channel membrane protein Aquaporin-1 (AQP) in rat aortic endothelial cells suggests a new possibility of water transport across the normal (non-leaky) endothelium, alongside the generally accepted paracellular route. Interestingly, we found that chemically blocking AQPs changes rat aortic wall Lp in a strongly pressure dependent manner. We then proposed a new theory that agrees well with this otherwise perplexing experimentally-observed pressure-dependence. One upshot of this theory is that it suggests that AQPs contributes about 30% to the phenomenological endothelial Lp at low transmural pressures.

In the present work we investigate the effect of AQPs on the overall transport of various species, like Horse Reddish Peroxidase (HRP) and LDL, across the vessel endothelium and its further spread in the vessel wall using the advection-diffusion model developed by Huang et al. (Journal of Biomechanical Engineering, vol 116, 1994, pp. 430-445) and later improved by Zeng et al. (American Journal of Physiology, Heart Circ Physiol, 302, 2012, pp. 1683-1699). We extend this model by incorporating the trancellular water flow through AQPs and use some important parameters like the hydraulic conductivity of the endothelium plus intima (Lp_e) and the corresponding intima thicknesses from our local filtration model mentioned above that allows us to calculate these important parameters at different pressures, something which was not considered in earlier models. The goal of this model is to investigate if increasing the endothelial AQP expression – say, pharmacologically or via diet, leading to higher endothelial Lp (which reduces SI compression causing higher overall vessel wall Lp), can decrease the overall concentration of macromolecules in the sub-endothelial space and thereby slow down kinetics of its binding to SI ECM, the triggering event in lesion formation and subsequent pre-atherosclerotic events. Our preliminary findings suggest that increasing transcellular transport by increasing AQP expression lowers the concentration of HRP in sub-endothelial space and by October we should be able to make definitive statements as to the analogous effects that could be observed for more biologically relevant macromolecules like LDL.