(726b) Mathematical Modeling of Transendothelial Water Transport and the Resulting Oncotic Paradox: Possible Link to Early Atherosclerosis?

Macromolecular transport across the vessel wall, apparently the earliest pre-atherosclerotic event, is known to occur due to advection by transmural (i.e., across the vessel wall) pressure driven plasma (water and solutes) transport through temporary leaky junctions around rare endothelial cells that are either dying or dividing. This convective transport is characterized by a wall parameter, the hydraulic conductivity (Lp), defined as the ratio of transmural water flux to the transmural pressure difference. It is important to understand the transmural water transport in detail because, on one hand, it advects macromolecules like low-density lipoprotein (LDL) into the arterial subendothelial intima (SI) through these leaks and spreads it there, thereby giving it the chance to bind to extra cellular matrix and possibly trigger the start of atherosclerotic lesion formation. On the other hand, the overall water flow across the normal endothelium dilutes LDL's local SI concentration, thereby likely slowing binding kinetics, and washes not-yet-bound lipid further into the wall. Our group's discovery of the presence of Aquaporin-1 (AQP) in rat aortic endothelial cells suggests a new possibility of water transport across the endothelial cell, alongside the generally accepted paracellular route. Interestingly, we find that blocking AQPs changes wall Lp in a strongly pressure dependent manner. We have proposed a new theory to explain the perplexing experimentally-observed pressure-dependent effect of AQP-blocking on the Lp of rat aorta. Our results agree well with the experimental data and suggest that AQPs contribute about 30% to the phenomenological endothelial Lp at low transmural pressures. However, given the isotonic lumen, this AQP-mediated pure water inflow into the arterial SI should set up an oncotic pressure gradient ΔΠ that opposes the ΔP -driven flow through the cell. How then could trans-AQP flow persist for many hours, as indicated by chemical blocking of AQP experiments? To resolve this paradox, we have extended our theory for water transfer across the vessel wall to also include the mass transfer of oncotically active small solutes like albumin. This addition non-linearly couples the mass transfer, the fluid flow and the wall mechanics. We employ numerical finite difference scheme to solve the system of non-linearly coupled PDEs. Our results suggest that the mixing of hypotonic fluid exiting the AQPs with isotonic fluid coming in through EC junctions leads to a steady transendothelial oncotic situation consistent with the observed transendothelial flow.