Piezo1 couples fluid shear stress to adaptive genome dynamics by integrating cytoplasmic-nuclear mechanotransduction

Fluid shear stress (FSS) regulates endothelial morphology and function through flow-responsive gene expression programs. Yet, how mechanical forces are transmitted across cytoplasmic and nuclear compartments to regulate genome adaptive response remains unclear. Here, we show that FSS induces rapid nuclear remodeling characterized by nuclear compaction and apical nuclear indentations. These changes are driven by reorganization of perinuclear actin and microtubule cytoskeleton into apical linear cytoskeletal cables that constrain the nuclear surface. Concurrently, the mechanosensitive ion channel Piezo1 redistributes from the plasma membrane to these perinuclear deformations. Quantitative molecular imaging under flow reveals a transient adaptive cell state characterized by chromatin reorganization and epigenetic remodeling, accompanied by altered mobility of the flow-responsive transcription factor KLF2. Pharmacological inhibition of Piezo1 abolishes FSS-induced nuclear deformation and uncouples chromatin reorganization from KLF2 dynamic changes. Together, these findings reveal that endothelial mechanotransduction exploits physical principles of nuclear organization to regulate transcription factor behavior and adaptive genome responses across biological scales.