Atherosclerosis is responsible for over 50% of all deaths in the US and in all Western countries1. It appears to begin when low-density lipoproteins (LDLs) are transported, mainly by pressure driven convection, from the blood and deposited into the inner layers of high-pressure large and intermediate arteries. Subsequent events narrow these vessels, leading possibly to strokes and heart attacks. Permeability studies have shown that, at least over short time scales, macromolecules appear to cross the endothelium of these atherosclerotic prone vessels non-uniformly via rare focal leaks that are associated with transient leaky junctions of endothelial cells, some of which are either dying or dividing.2-4 Pressure-driven transmural water transport advects these macromolecules across the endothelium into the subendothelial intimal space and initially spreads them in a direction parallel to the endothelium away from the leakage sites. The overall water flux can drive and dilute the local macromolecular concentration causing them to spread away from the focal leaky regions, and eventually carrying them through the fenestra of the internal elastic lamella (IEL) and into the media. Since this water flux affects the local LDL concentration in the intima, it very likely affects the kinetics of LDL binding to the intima's extracellular matrix, which is believed to be one of the earliest events leading to lesion formations. The nature of this convective water flux is therefore a central factor in the prelesion events of atherosclerosis. It has traditionally been accepted that water crosses the endothelium paracellularly, that is through tight and leaky junctions, the former, due to their numbers, being far more important than the latter. Since 1990, however, a family of ubiquitous transmembrane proteins called aquaporins (AQP) have been identified. AQPs are very specific and facilitate very efficient transcellular water transport.5-13 It is therefore natural to ask whether AQPs are present in arterial endothelial cells and, if so, if their presence implies a transcellular function in transmural water transport. Such transport, if it indeed is present, would play an important role in LDL transport and binding kinetics in the subendothelial portion of the vessel wall. In this study, we use immunohistochemistry to identify and show the existence of Aquaporin-1 (AQP1) on the both the lumenal and ablumenal membranes of the rat aortic endothelial cells. The existence of these molecules suggests that they may play a role in the hydraulic conductivity (Lp) of the endothelium and that the vessel wall may actively control its AQP expression as a way of controlling its Lp in response to external conditions. Hypertension is a known risk factor for atherosclerosis. It is therefore conceivable that one external condition that influences a vessel's AQP expression is its transmural pressure. In this study, we both quantify and compare and examine the distribution of endothelial AQP1 in both normotensive and chronically hypertensive rat models. We also combine and compare these results with an ex-vivo study that examines AQP1 contribution to the aorta's hydraulic conductivity. We find that endothelial cells from chronically hypertensive rats appear to express far more AQP than their normotensive cousins and there is a significant contribution of aquaporin-1 to the endothelial hydraulic conductivity in large vessels. We suspect that vessels may be able to actively regulate their aquaporin expression in response to chronic hypertensive conditions in order to control their transmural transport processes. Improved understanding of these processes may lead to novel, preventative therapies.

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