(230au) Early Atherogenesis: How Blood-Pressure-Driven Flow and Membrane Proteins Influence Artery Wall Mechanics and Mass Transfer Across the Artery Wall

Atherosclerosis has long been the leading cause of death in the United States and all Western countries. It begins with the transmural (across the wall)-pressure (DP)-driven advection of macromolecular aggregates such as low-density lipoprotein (LDL) cholesterol from the blood across the monolayer of endothelial cells that lines the vessel and into the artery wall. Particles of the size of LDL (~22nm) cross the endothelium through the junctions around rare (~1/2000-5000) endothelial cells whose junctions are sufficiently wide and enter the wallâ??s thin subendothelial intima (SI) layer where they can bind to SI extracellular matrix (ECM) and accumulate. The blood pressure also drives much smaller molecules such as water and small solutes across the entire endothelium, much of it likely across the normal inter-endothelial tight junctions, and through the wall. This flow may be critical determinant of prelesion events since it can dilute the local SI LDL concentration, which likely slows its kinetics of binding to ECM, and flushes unbound LDL from the wall.

We have earlier shown that bovine and rat aortic endothelial cells (ECs) express the membrane water channel protein, aquaporin-1 (AQP1) and that up/down-regulating the number of EC AQP1s increases/decreases the transmural water flow at fixed DP, i.e., increases/decreases the ratio, the hydraulic conductivity, Lp, of flux to DP. Thus a portion of the transmural water flow goes through the cells, in parallel with the portion that goes between them. Further we have shown earlier that at fixed EC AQP1 expression, Lp vs DP is flat at low DP, drops over a narrow DP window and then remains flat to high DP, but the position of this window depends on DEC AQP1 expression. We have shown that this Lp-dependence at fixed EC AQP1 is due to compression of the SI region of the vessel wall, which blocks certain fluid transport pathways into deeper regions of the wall. Here we present a hydrodynamic theory to explain the EC AQP! dependence of the position of the transition window and how to shift this window. Time permitting, we shall show how using this flow field and the hgihg AQP1 selectivity for pure water transport in an advective-diffusion theory for small solute, e.g., albumin, transport yields a measurable oncotic effect. The theory shows how measured Lp values include mass transfer effects, how one can extract intrinsic Lp values from these measurements and a strategy to potentially slow pre-lesion lipid entrainment in the artery wall.