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. [Display omitted] •Pipeline to extract geometrically faithful nuclear and cytoplasmic stiffnesses•Changes to nuclear and cytoplasmic stiffnesses alter nuclear mechanosensing•The critical parameter for shear sensing is the nuclear/cytoplasmic stiffness ratio•Transfer relation persists under dynamic loading and cellular viscoelasticity Endothelial cell shear mechanosensing, how the cells respond to fluid forces, is critical for function. However, how the mechanical properties of cells contribute to this process remains unclear. With recent understanding of the nucleus as a mechanosensor, we built a pipeline to extract the mechanical properties of the cytoplasm and nucleus to study computationally how they affect shear stress transmission to the nucleus. Our in silico results demonstrate that the critical parameter determining shear stress transfer to the nucleus is the ratio between the nuclear and cytoplasmic stiffnesses. This transfer relation provides a global picture of nuclear mechanosensing, remaining consistent under different loading conditions and when incorporating viscoelasticity. Our results provide fundamental insight into mechanosensing as a holistic process of many interacting mechanical components. Elucidating nuclear mechanosensing will drive our understanding of physiology and disease states. The nucleus has emerged as an important mechanosensor. We used a correlative atomic force microscopy/super-