# Evidence for Drop‐Like Nuclear Deformation in Sheared Endothelial Monolayers

## TL;DR

Blood flow smooths endothelial cells by removing poorly spread cells, with nuclear shape changes governed by constant volume and surface area, and YAP activation linked to cell spreading.

## Contribution

Demonstrates that nuclear deformation under shear stress follows a drop-like model with constant volume and surface area, and revises the mechanism of YAP nuclear localization.

## Key findings

- Nuclear volume and surface area remain constant under shear stress, supporting the drop model.
- Lamin A/C provides nuclear surface tension and maintains shape regularity.
- YAP nuclear localization is driven by increased cell spreading and cytoskeletal tension, not nuclear deformation.

## Abstract

Shear stress imparted by blood flow tends to smoothen endothelial monolayers, a response classically attributed to reduced nuclear height and nuclear reorientation along flow. However, the mechanical basis remains unclear. Here, we tested predictions of the nuclear drop model—which posits that nuclear shape changes occur at constant volume and surface area—in human umbilical vein endothelial cells (HUVECs) under physiological shear stress. HUVEC nuclear morphologies varied from smooth, flat nuclei to wrinkled, tall ones. Applying shear stress reduced the frequency of tall, wrinkled nuclei, explaining the population‐level decrease in nuclear height. Lamin A/C–depleted nuclei are highly irregular and failed to recover shapes postindentation on PDMS microposts, suggesting that lamin A/C confers nuclear surface tension. Nuclear volume and surface area remained constant under shear, consistent with the drop model, and a computational model based on these constraints successfully predicted observed nuclear shapes. Neither lamin A/C nor lamin B1 depletion prevented shear‐induced YAP nuclear localization; instead, shear detached poorly spread cells, increasing spreading, focal adhesion assembly, and cytoskeletal tension in the remaining cells, thereby promoting YAP nuclear localization. These findings revise classical interpretations of flow‐induced endothelial smoothing and show that flow‐induced YAP nuclear localization results from increased cell spreading rather than nuclear deformation.

Physiological shear stress smoothens endothelial monolayers by selectively eliminating less‐spread cells with tall, wrinkled nuclei. Nuclear volume and surface area remain constant, consistent with drop‐like deformation governed by geometric constraints. Lamin A/C provides nuclear surface tension, while shear‐induced YAP nuclear localization arises indirectly from enhanced spreading, focal adhesion assembly, and cytoskeletal tension.