Astrocytes sense glymphatic-level shear stress through the interaction of sphingosine-1-phosphate with Piezo1.

Astrocyte endfeet enwrap brain vasculature, forming a boundary for perivascular glymphatic flow of fluid and solutes along and across the astrocyte endfeet into the brain parenchyma. We evaluated astrocyte sensitivity to shear stress generated by such flow, finding a set point for downstream calcium signaling that is below about 0.1 dyn/cm2. This set point is modulated by albumin levels encountered in cerebrospinal fluid (CSF) under normal conditions and following a blood-brain barrier breach or immune response. The astrocyte mechanosome responsible for the detection of shear stress includes sphingosine-1-phosphate (S1P)-mediated sensitization of the mechanosensor Piezo1. Fluid flow through perivascular channels delimited by vessel wall and astrocyte endfeet thus generates sufficient shear stress to activate astrocytes, thereby potentially controlling vasomotion and parenchymal perfusion. Moreover, S1P receptor signaling establishes a set point for Piezo1 activation that is finely tuned to coincide with CSF albumin levels and to the low shear forces resulting from glymphatic flow.