Stretch and flow at the gliovascular interface: high-fidelity modelling of the mechanics 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 (ECS) 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. Significance Perivascular spaces, formed by astrocyte endfeet wrapping the vasculature, are high-conduit pathways for brain fluid flow and clearance. Vascular pulsations drive this flow, but the resulting mechanical interactions at the gliovascular interface remain largely unknown. We introduce a computational model of the solid and fluid mechanics here, using realistic geometries to capture intricate astrocyte morphology at the subcellular level. Our simulations reveal that changes in perivascular composition - associated with aging or neurodegenerative diseases - fundamentally alter mechanical coupling, potentially impeding fluid transport. This work provides a mechanistic framework for understanding brain clearance and constitutes a foundational model for computational studies of mechanical forces in the nervous system. - astrocyte endfeet - mechanics - in-silico modelling - pulsatility - fluid exchange Competing Interest Statement The authors have declared no competing interest. Footnotes M.C., R.E., and M.E.R. conceived and designed the project. M.C. developed the software and conducted the experiments. M.C. analyzed the results and prepared the figures. M.C. R.E. and M.E.R. wrote the manuscript. All authors edited, reviewed and approved the manuscript. The authors declare no competing interests.. shorten and fit to PNAS template, add supplementary