Atherosclerosis starts with transmural (transwall) pressure-driven advective transport of blood-borne low-density lipoprotein (LDL) cholesterol across rare endothelial cell (EC) monolayer leaks into the arterial subendothelial intima (SI) wall layer where they can spread, bind to extracellular matrix and seed lesions. The local SI LDL concentration, which governs LDL’s binding kinetics, depends on the overall diluting transmural liquid flow. Transmural pressures typically compress the SI at physiological pressures, which keeps this flow low. Nguyen et al. (2015) showed that aortic ECs express the water channel protein aquaporin-1 (AQP1) and the transEC (δP) portion of the transmural (ΔP) pressure difference drives, in parallel, water across AQP1s and plasma across interEC junctions. Since the lumen is isotonic, selective AQP1-mediated water flow should quickly render the ECs’ lumen side hypertonic and the SI hypotonic; resulting transEC oncotic pressure differences, δπ, should oppose δP and quickly halt transEC flow. Yet Nguyen et al.’s (2015) transAQP1 flows persist for hours. To resolve this paradox, we extend our fluid filtration theory Joshi et al. (2015) to include mass transfer for oncotically active solutes like albumin. This addition nonlinearly couples mass transfer, fluid flow and wall mechanics. We simultaneously solve these problems at steady state. Surprisingly it finds that media layer filtration causes steady SI to exceed EC glycocalyx albumin concentration. Thus δπ reinforces rather than opposes δP, i.e., it sucks water from, rather than pushing water into the lumen from the SI. Endothelial AQP1s raise the overall driving force for flow across the EC above δP, most significantly at pressures too low to compress the SI, and they increase the ΔP needed for SI compression. This suggests the intriguing possibility that increasing EC AQP1 expression can raise this requisite compression pressure to physiological values. That is, increasing EC AQP1 may decompress the SI at physiological pressures, which would significantly increase SI thickness, flow and subsequently SI LDL dilution. This could retard LDL binding and delay preatherosclerotic lesion onset. The model also predicts that glycocalyx-degrading enzymes decrease overall transEC driving forces and thus lower, not raise, transmural water flux.

动脉粥样硬化开始于跨壁（transwall）压力驱动的血源性低密度脂蛋白（LDL）胆固醇平流运输穿过罕见的内皮细胞（EC）单层泄漏到动脉内皮下内膜（SI）壁层，在那里它们可以扩散，结合到细胞外基质和种子损伤。控制 LDL 结合动力学的局部 SI LDL 浓度取决于整体稀释透壁液体流量。跨壁压力通常会在生理压力下压缩 SI，从而使流量保持在较低水平。阮等。(2015) 表明主动脉 ECs 表达水通道蛋白水通道蛋白-1 (AQP1) 和跨壁的 transEC ( δP ) 部分 (Δ P) 压力差驱动，并行地，水穿过 AQP1s 和等离子体穿过 interEC 连接点。由于内腔是等渗的，选择性 AQP1 介导的水流应迅速使 EC 的内腔侧高渗和 SI 低渗；由此产生的 transEC 渗透压力差异，δπ，应该反对δP并迅速停止 transEC 流程。然而 Nguyen 等人 (2015) 的 transAQP1 流持续数小时。为了解决这个悖论，我们扩展了我们的流体过滤理论 Joshi 等人。(2015) 包括像白蛋白这样的肿瘤活性溶质的传质。这种添加非线性耦合传质、流体流动和壁力学。我们在稳定状态下同时解决这些问题。令人惊讶的是，它发现介质层过滤导致稳定的 SI 超过 EC 糖萼白蛋白浓度。因此δπ加强而不是反对δP，即它从 SI 吸水而不是将水推入管腔。内皮 AQP1 将流过 EC 的整体驱动力提高到δP以上，最显着的压力太低而无法压缩 SI，并且它们会增加SI 压缩所需的ΔP 。这表明增加 EC AQP1 表达可以将这种必要的压缩压力提高到生理值的有趣可能性。也就是说，增加 EC AQP1 可能会在生理压力下减压 SI，这将显着增加 SI 厚度、流量和随后的 SI LDL 稀释。这可以延缓 LDL 结合并延迟动脉粥样硬化前病变的发生。该模型还预测，糖萼降解酶会降低整体 transEC 驱动力，从而降低而不是提高透壁水通量。