This article explores the relationship between hemodynamic forces and atherosclerosis, with a focus on the role of HEG1 as a sensor of shear stress on endothelial cells. It explains that disturbed shear stress in certain areas of blood vessels is associated with the development of atherosclerotic plaques, while laminar shear stress is protective. The study by Tamargo et al. identifies HEG1 as the sensor that activates the ERK pathway and leads to the activation of KLF2, which is important for vascular health. The article also discusses the role of HEG1 in regulating the activation of KLF2/4 and the MEKK3 cascade in endothelial cells under laminar flow conditions. The authors demonstrate that HEG1 is a cell surface sensor that promotes the activation of KLF2/4 and regulates the MEKK3 cascade, and that suppression of the MEKK3 cascade is controlled by KRIT1 in a HEG1-dependent manner. The findings suggest that HEG1 plays a crucial role in maintaining endothelial homeostasis and protecting against atherosclerosis, but there are still unanswered questions about the mechanisms of HEG1 and KRIT1 secretion, as well as the relationship between HEG1 and NOTCH1. [Extracted from the article]