2026/07/13 by Tanran Zhang, Shixin Xu
#physics.med-ph #physics.bio-ph
Experimental studies show that impaired aquaporin-4 (AQP4) function or polarization reduces glymphatic clearance, whereas recent mechanical models suggest that pressure-driven water exchange occurs mainly through inter-endfoot gaps rather than directly across the AQP4-rich membrane. To reconcile these observations, we develop a reduced arterial-ECS-venous multicompartment model coupling vascular forcing, PVS deformation, AQP4-mediated endfoot water exchange, dynamic inter-endfoot gap regulation, and tracer transport. The model shows that cardiac-like oscillations generate strong bidirectional exchange but weak net clearance, whereas asymmetric vasodilation enhances directional transport by reducing recovery-phase backflow. Although the direct PVS-facing membrane flux remains much smaller than the gap-mediated flux, PVS-facing AQP4 transport can substantially influence clearance by altering the pressure--volume balance of the coupled Pa-A-Ea network. Endfoot-volume-to-gap coupling provides an additional modulation of gap conductance. Under symmetric slow-vasomotion forcing, reducing effective PVS-facing AQP4 permeability decreases cumulative venous output by about 40%. We further examine aging-associated reductions in vessel motion, altered PVS mechanical coupling, and impaired AQP4 function. Their combined effects substantially suppress gap opening and venous-directed clearance, reducing cumulative venous output by approximately 63% and 74% in representative moderate and advanced aging-like cases. These results suggest that AQP4 need not carry the dominant hydrostatic flux to regulate clearance, because PVS-facing AQP4 transport alters the hydraulic driving forces of the gap pathway, while endfoot-volume feedback provides an additional modulation of gap conductance.