AQP4 Regulates Gap-Dominated Glymphatic Clearance through Dynamic Gliovascular Coupling

Abstract

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.