Molecular Mechanisms of Hemodynamic Mechanotransduction in Endothelial Cells

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Summary of  iScience  https://doi.org/10.1016/j.isci.2025.113879 
Dr. Oscar M J A Stassen  et al.

Points

Investigators used proximity labeling and shear stress platforms to identify how endothelial cells translate the physical force of blood flow into specific molecular signaling pathways for vessel stability.
The study identified the motor protein Myo1c as a flow-sensitive transporter that binds to Jagged1 under static conditions but releases it once the cell detects hemodynamic shear stress.
Experiments involving Myo1c knockouts proved that this protein is essential for the proper polarization and internal transport of signaling ligands that allow neighboring vascular cells to coordinate growth.
Research further revealed that Jagged1 performs a dual role by acting both as a classical Notch receptor activator and as a direct trigger for internal force-sensing mechanotransduction pathways.
These molecular insights into vascular adaptation provide new clinical opportunities for regenerative medicine and strategies to target the specific blood vessels that provide nutrients to cancerous tumors.

Summary

This research evaluated the molecular mechanisms by which endothelial cells transduce hemodynamic shear stress into biological signals to maintain vascular stability. Specifically, investigators focused on the spatial organization of the Notch ligand Jagged1, a protein essential for coordinating vessel growth and mural cell recruitment. Using proximity labeling with Jagged1-APEX2 and orbital shaker platforms to simulate shear stress, the study sought to identify the intracellular transporters responsible for the flow-dependent localization of these morphogenic signaling proteins.

The findings identified the molecular motor protein Myo1c as a critical, flow-sensitive regulator of Jagged1 trafficking. Under static conditions, coimmunoprecipitation confirmed a robust interaction between Myo1c and Jagged1, which maintained membrane levels of the ligand. However, exposure to shear stress significantly reduced this interaction, triggering the release of Jagged1 and its subsequent nucleograde transport. Myo1c knockout experiments further demonstrated that without this motor protein, the precise polarization and internalization of Jagged1 in response to flow were inhibited, disrupting the cell’s ability to communicate mechanical cues to neighboring tissues.

Beyond its role as a Notch ligand, the research uncovered that Jagged1 acts as a direct mediator in mechanotransduction pathways, independent of its classical receptor-activation function. This dual utility allows endothelial cells to simultaneously sense physical forces from blood flow and initiate biological adaptation. These discoveries provide a detailed molecular framework for understanding vascular morphogenesis and stability. By identifying Myo1c and Jagged1 as central components of the body’s hemodynamic control system, the study suggests new therapeutic targets for managing cardiovascular disease, improving regenerative medicine, and inhibiting the pathological angiogenesis associated with tumor growth

Link to the article: https://pubmed.ncbi.nlm.nih.gov/41321631/

References

Stassen, O. M. J. A., Virtanen, N., Lin, K.-L., Suarez Rodriguez, F., Heijmans, M. J. M., Zhao, F., Corthals, G. L., Bouten, C. V. C., & Sahlgren, C. M. (2025). Mechanosensitive interactions between Jag1 and Myo1c control Jag1 trafficking in endothelial cells. iScience, 28(12), 113879. https://doi.org/10.1016/j.isci.2025.113879