Stretch and flow at the gliovascular interface: High-fidelity modeling of astrocyte endfeet

Abstract

Astrocyte endfeet form a near-continuous sheath around the brain’s vasculature, defining the perivascular spaces (PVS) that are crucial for brain fluid flow and solute transport. Yet, their precise physiological role remains poorly understood. Using 3D electron microscopy data, we created a high-fidelity poroelastic computational model of an arteriole segment with surrounding endfeet and parenchyma to investigate tissue displacement and fluid flow within the PVS, endfeet, and extracellular space in response to blood vessel pulsations. Our model predicts that arteriole dilations compress the PVS while expanding the overall endfoot sheath volume due to tangential stretch. Moreover, fluid exchange primarily occurs through inter-endfoot gaps, driven by pressure differences, rather than across the aquaporin-4 (AQP4) rich endfoot membrane. PVS stiffness critically modulates these dynamics: Increased stiffness of the PVS, for instance, due to vessel pathology or aging, would minimize or even reverse fluid exchange at the gliovascular interface. While AQP4 mediated water movement has a negligible impact on pulsation-driven mechanics, it significantly enhances osmotically driven fluid flow. Overall, our findings elucidate the complex balance of forces governing gliovascular mechanics and suggest that PVS composition strongly influences endfoot-parenchymal fluid exchange.