Journal ArticleEvidence for Drop‐Like Nuclear Deformation in Sheared Endothelial MonolayersMohajeri, Mohammad [Department of Biomedical Engineering Texas A&M University College Station Texas USA] (ORCID:0009000150209596); Wang, Ting‐Ching [Artie Mcferrin Department of Chemical Engineering Texas A&M University College Station Texas USA]; Agarwal, Pooja [Department of Electrical Engineering & Computer Science University of California Berkeley California USA]; Kaur, Simran [Department of Biomedical Engineering Texas A&M University College Station Texas USA] (ORCID:0009000469667142); Kumar, Ankit [Department of Biomedical Engineering Texas A&M University College Station Texas USA]; Dickinson, Richard B [Department of Chemical Engineering University of Florida Gainesville Florida USA]; Jain, Abhishek [Department of Medical Physiology Texas A&M Health Science Center Bryan Texas USA]; Lele, Tanmay P [School of Engineering Medicine Texas A&M University Houston Texas USA] (ORCID:0000000185741251)<title>ABSTRACT</title> <p>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.</p>Wiley2026-02-0110676432Small22101613-6810https://doi.org/10.1002/smll.2025065362412520; 2226157National Science Foundation