City College New York

Atherosclerosis is the leading cause of death, both above and below age 65, in the United States and all Western countries. Its earliest prelesion events appear to be the transmural (across the wall)-pressure (DP)-driven advection of large molecules such as low-density lipoprotein (LDL) cholesterol from the blood into the inner wall layers across the monolayer of endothelial cells that tile the blood-wall interface. This transport occurs through the junctions around rare (~one cell every few thousand) endothelial cells whose junctions are wide enough to allow large molecules to pass. These LDL molecules can bind to extracellular matrix (ECM) in the wall’s thin subendothelial intima (SI) layer and accumulate there. On the other hand, the overall transmural water flow can dilute the local intima LDL concentration, thereby slowing its kinetics of binding to ECM, and flushes unbound lipid from the wall. An understanding of the nature of this water flow is clearly critical.

            We have found that rat aortic endothelial cells express the ubiquitous membrane water-channel protein aquaporin-1 (AQP), and that blocking its water channel or knocking down its expression significantly reduces the apparent hydraulic conductivity Lp of the endothelium and, consequently of the entire wall. This decrease has an unexpected and strong DP -dependence. We present a fluid mechanics theory based on the premise that DP compacts the SI, which, as we show, lowers its Lp. The theory shows that blocking or knocking down AQP flow changes the critical DP at which this compaction occurs and explains our observed dependence of Lp on DP. Such compaction may affect lipid transport and accumulation in vivo. However, AQP’s sharp water selectivity gives rise to an oncotic paradox: the SI should quickly become hypotonic and shut down this AQP flow. The mass transfer problem resolve this paradox. The importance of aquaporin-based, rather than simply junctional water transport is that transport via protein channels allows for the possibility of active control of vessel Lp by up- or down-regulation of protein expression. We show that rat aortic endothelial cells significantly change their AQP numbers in response to chronic hypertension (high blood pressure), which may help explain the as yet poorly-understood fact that hypertension correlates with atherosclerosis. We also consider lowering AQP numbers as a strategy to affect disease progression.