AI 中文总结
研究类淋巴系统清除机制，开发多隔室模型耦合多种因素，发现心脏样振荡、非对称血管舒张等对清除的影响，以及衰老相关变化对清除的抑制作用，揭示AQP4通过改变水力驱动力和终足体积反馈调节清除率。
AI 中文摘要
实验研究表明水通道蛋白4（AQP4）功能或极化受损会降低类淋巴系统清除率，而近期力学模型表明压力驱动的水交换主要通过终足间隙而非直接穿过富含AQP4的膜。为调和这些观察结果，我们开发了一个简化的动脉-细胞外基质-静脉多隔室模型，耦合血管强迫、PVS变形、AQP4介导的终足水交换、动态终足间隙调节和示踪剂运输。模型显示心脏样振荡产生强烈的双向交换但净清除率弱，而非对称血管舒张通过减少恢复相回流增强定向运输。在固定间隙条件下，间隙介导的通量比直接AQP4介导的通量大约大二十倍。然而，AQP4可通过终足体积反馈和间隙电导的动态调制间接强烈调节清除率。在对称慢血管运动强迫下，降低有效AQP4功能会使累积静脉输出减少约40%。我们进一步研究了与衰老相关的血管运动减少、PVS机械耦合改变和AQP4功能受损。它们的综合作用显著抑制间隙开放和静脉定向清除，在代表性的中度和晚期衰老样病例中使累积静脉输出减少约63%和74%。这些结果表明AQP4无需携带主要的静水压通量来调节清除率，因为面向PVS的AQP4转运改变了间隙途径的水力驱动力，而终足体积反馈提供了间隙电导的额外调制。
英文摘要
Aquaporin-4 (AQP4) is enriched at perivascular astrocytic endfeet, and impaired AQP4 function or localization is associated with reduced glymphatic transport. However, mechanical models suggest that pressure-driven exchange across the gliovascular interface occurs predominantly through inter-endfoot gaps rather than directly through the AQP4-rich membrane. How AQP4 regulates clearance in such a gap-dominated system remains unclear. We develop a reduced arterial PVS-ECS-venous PVS model coupling vascular deformation, AQP4-mediated endfoot water exchange, dynamic inter-endfoot gap regulation, and tracer transport. Cardiac-like oscillations generate strong bidirectional exchange but weak net clearance, whereas asymmetric vasodilation enhances directional transport by suppressing recovery-phase backflow. Dynamic gap regulation provides additional hydraulic rectification. Although gap-mediated flux is much larger than direct AQP4-mediated flux, PVS-facing AQP4 substantially affects clearance by altering the pressure--volume balance and hence the driving force for the dominant gap pathway. Reducing PVS-facing AQP4 permeability, or redistributing AQP4 away from the PVS-facing membrane at fixed total conductance, reduces cumulative venous output by about 40\%. Aging-like changes in vascular motion, PVS mechanical coupling, and perivascular AQP4 enrichment further compound this impairment. These results suggest that AQP4 regulates gap-dominated glymphatic clearance through dynamic hydraulic coupling at the gliovascular interface.
