(494e) Chronic Hypertension Increases Aortic Endothelial Hydraulic Conductivity By Upregulating Endothelial Aquaporin-1 Expression

Blood pressure drives the advective transport of large solutes such as LDL cholesterol from the blood through rare widened inter-endothelial junctions into the vessel wall where they can bind to extracellular matrix in the subendothelial intima (SI) layer; this is believed to be the earliest event in atherogenesis. Water and small molecules can also cross the far more numerous normal endothelial junctions and, we have previously shown, transcellularly via aquaporin-1 membrane proteins that the endothelial cells avidly express. This flow can potentially dilute LDL concentration that has built up in the SI and slow its kinetics of binding there; so increasing this water flow may be beneficial in slowing early atherogenesis. It is first worth asking why the endothelial cells express this protein if water can traverse the endothelium paracellularly.

            In addition to other functions, e.g., NO transport, of aquaporin, it may be the case that regulating aquaporin expression allows the vessel/cells to actively control both the force/area that the endothelial cells feel and the water flux that they allow across them in response to changes in environmental conditions, e.g., chronic hypertension. We have developed a theory that relates aquaporin expression to both endothelial and vessel wall hydraulic conductivity. It predicts how SI thickness and vessel hydraulic conductivity should vary with both aquaporin expression and transmural pressure. We test this theory on two high-renin rat models of hypertensive rat models, one genetic (spontaneously hypertensive rats and their normotensive cousins, the Wystar Kyoto rats) and Sprague-Dawley rats, some of which have been made hypertensive by renovascular surgery. In both cases aquaporin-1 expression (measured by quantitative immunohisto­chemistry) of the hypertensives is 2-3 times that of the normotensives and, at lower pressures, the hydraulic conductivity of the hypertensives is 2-3 times that of the normotensives. Our theory explains this pressure dependence. In addition, acute chemical upregulation of endothelial aquaporin-1 expression (by two hour forskolin treatment) has a similar and consistent effect on both aquaporin-1 expression and endothelial hydraulic conductivity, despite the fact that medial hydraulic conductivity in chronic hypertensives is far lower than in acutely treated normotensives. Upregulated aquaporin-1 expression and function may thus be a response to hypertension that critically determines conduit artery vessel wall viability and long-term susceptibility to atherosclerosis.