Disrupted stiffness ratio alters nuclear mechanosensing

The ability of endothelial cells to sense and respond to dynamic changes in blood flow is critical for vascular homeostasis and cardiovascular health. The mechanical and geometric properties of the nuclear and cytoplasmic compartments affect mechanotransduction. We hypothesized that alterations of these parameters have mechanosensory consequences. Using atomic force microscopy and mathematical modeling, we assessed how nuclear and cytoplasmic compartment stiffnesses modulate shear stress transfer to the nucleus in aging endothelial cells. Our computational studies revealed that the critical parameter controlling shear transfer is not the individual mechanics of these compartments but the stiffness ratio between them. Replicatively aged cells had a reduced stiffness ratio, attenuating shear transfer, while the ratio was not altered in a genetic model of accelerated aging. We provide a theoretical framework suggesting that dysregulation of the shear stress response can be uniquely imparted by relative mechanical changes in subcellular compartments.