Cell adhesion molecule interaction with Piezo1 channels is a mechanism for sub cellular regulation of mechanical sensitivity

The discovery of Piezo1 channels as force sensors with roles in the endothelial response to fluid flow has appeared contradictory to earlier work suggesting mediation by a triad of cell adhesion molecules (CD31 and VE-cadherin) and vascular endothelial growth factor receptor 2 (VEGFR2). Here we propose an explanation. Stimulated emission depletion microscopy revealed physical proximity between Piezo1 and CD31 primarily at cell junctions. Förster resonance energy transfer measured by fluorescence lifetime imaging showed that the proteins approached to less than 10 nm. Substitution of a tyrosine residue at the distal C-terminus of CD31 prevented the interaction, suggesting intracellular association. The extracellular N-terminus also interacted, but exclusively at cell junctions. There was proximity between Piezo1 and VE-cadherin but not VEGFR2. Interaction with VE-cadherin was flow-dependent, consistent with additional recruitment after flow-sensing. CD31 suppressed mechanical sensitivity of Piezo1 channels and interacted with N-terminal Piezo1 propeller arms implicated in force sensing. The data suggest partnership between Piezo1 and adhesion molecules for sub cellular tuning of force response.