Aquaporin-1 shifts the critical transmural pressure to compress the aortic intima and change transmural flow: theory and implications.

Transmural-pressure (ΔP)-driven plasma advection carries macromolecules into the vessel wall, the earliest pre-lesion atherosclerotic event. The wall's hydraulic conductivity, LP, the water flux to ΔP ratio, is high at low pressures, rapidly decreases and remains flat to high pressures (30, 1, 23, 19) due to pressure-induced subendothelialintima (SI) compression that causes endothelial cells to partially block internal elastic laminar fenestrae. Nguyen et al. (19) showed that rat and bovine aortic endothelial cells express the membrane protein aquaporin-1 (AQP1) and transmural water transport is both transcellular and paracellular. They found that LP lowering by AQP1 blocking was perplexingly ΔP-dependent. We hypothesize that AQP1 blocking lowers average SI pressure; therefore a lower ΔP achieves the critical force/area on the endothelium to partially block fenestrae. To test this hypothesis, we improve Huang et al.'s (10) approximate model and extend it by including transcellular AQP1 water flow. Results confirm observation in (19): wall LP and water transport decrease with AQP1 disabling. It predicts (1) low-pressure LP experiments correctly; (2) AQP1s contribute 30-40% to both the phenomenological endothelial+SI and intrinsic endothelial LP; (3)the force on the endothelium for partial SI decompression with functioning AQP1s at 60 mmHg equals that on the endothelium at ~43 mmHg with inactive AQP1s; (4) increasing endothelial AQP1 expression increases wall LP and shifts the ΔP regime where LP drops significantly to higher ΔP. Thus AQP1 up-regulation (elevated wall LP) might dilute and slow low density lipoprotein binding to SI extracellular matrix, which may be beneficial for early atherogenesis.