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A noncanonical role for Jagged1 in endothelial mechanotransduction

Freddy Suarez Rodriguez Orcid Logo, Noora Virtanen, Elmeri Kiviluoto, Rob C. H. Driessen, Feihu Zhao Orcid Logo, Carlijn V. C. Bouten, Oscar M. J. A. Stassen, Cecilia M. Sahlgren Orcid Logo

The FEBS Journal

Swansea University Author: Feihu Zhao Orcid Logo

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DOI (Published version): 10.1111/febs.70466

Abstract

The Notch signaling pathway plays a crucial role in regulating endothelial biology. Notch signaling is sensitive to hemodynamic forces and governs mechanically driven cardiovascular development, physiology, and remodeling. However, the mechanisms by which mechanical forces integrate with the Notch p...

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Published in: The FEBS Journal
ISSN: 1742-464X
Published: 2026
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URI: https://cronfa.swan.ac.uk/Record/cronfa71485
Abstract: The Notch signaling pathway plays a crucial role in regulating endothelial biology. Notch signaling is sensitive to hemodynamic forces and governs mechanically driven cardiovascular development, physiology, and remodeling. However, the mechanisms by which mechanical forces integrate with the Notch pathway remain largely unknown. Here, we uncover a noncanonical role for the Notch ligand protein jagged-1 (Jagged1) in regulating the activity of mechanosensitive kinases in endothelial cells. We show that shear stress induces expression and relocalization of Jagged1 to cell junctions downstream of flow. Jagged1 expression under stress demonstrates magnitude dependence, and peaks at 0.8–1 Pa without impacting the Notch-activation potential of Jagged1. Jagged1 also regulates the activity of mechanosensitive kinases. Deletion of Jagged1 reduces the activity of vascular endothelial growth factor receptor 2 (VEGFR2) and mitogen-activated protein kinase (ERK) in vitro and diminished ERK activity in zebrafish embryos without affecting canonical Notch signaling. Furthermore, direct physical stimulation of Jagged1 using antibody-conjugated beads triggers the activation of VEGFR2 and ERK, mediated by Jagged1-induced proto-oncogene tyrosine-protein kinase Src activation. Taken together, we demonstrate a previously unknown noncanonical role for Jagged1 as a regulator of the activity of pathways involved in endothelial mechanotransduction.
Keywords: endothelial cells; hemodynamic forces;jagged1; mechanotransduction; notch signaling
College: Faculty of Science and Engineering
Funders: European Research Council (ERC) ERC-CoGNo 771168 (ForceMorph). European Research Council(ERC) ERC-SynG No 101167065 (Making Blood). Research Council of Finland, Center of Excellence,decision number #374179 (CoEIMMENs). ResearchCouncil of Finland, decision number #316882(SPACE). Research Council of Finland, decision num-ber #330411 (SignalSheets). Research Council of Fin-land, decision number #336355 (Solutions for Healthat ˚Abo Akademi University). Research Council of Fin-land, decision number #337531 and #357911(InFLAMES Flagship Program). Abo Akademi Uni-versity Foundation’s Centers of Excellence in CellularMechanostasis (CellMech) and Bioelectronic Activa-tion of Cell Functions (BACE).

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