Hydrostatic pressure reduces the mechanosensitivity of cell migration.

Cells sense and respond to diverse physical cues as they migrate toward distant sites. While much is known about the roles of cellular molecules in the regulation of mechanosensitivity, our understanding of how extracellular cues influence this property remains limited. Here, we show that prolonged exposure to elevated, yet (patho)physiologically relevant, extracellular hydrostatic pressure decreases migration sensitivity to substrate stiffness, fluid viscosity, fluid forces, and hydraulic resistance. Reduced mechanosensitivity can persist for days after the high-pressure cue is removed, indicating that cells retain a memory of hydrostatic pressure. Mechanistically, high pressure down-regulates the Rho/MRTF/SRF pathway, activating a myosin II-independent mechanosensing mechanism that shifts the maximum cell speed toward stiffer substrates, as predicted mathematically and demonstrated experimentally. Stiffer substrates increase migration of preconditioned cells by strengthening focal adhesions and redistributing them to the cell periphery to support Arp2/3-dependent lamellipodia extension. Collectively, hydrostatic pressure reprograms the mechanosensing machinery to drive lasting effects on cell mechanosensitivity.