A non-canonical role for Jagged1 in endothelial mechanotransduction

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 non-canonical role for the Notch ligand Jagged1 in regulating the activity of mechanosensitive kinases in endothelial cells. We show that stress induces expression and relocalization of Jagged1 to cell junctions downstream of flow. Jagged1 expression under stress demonstrates magnitude dependence and peaks at 0.8-1Pa without impacting Jagged1s Notch-activation potential. On the contrary Jagged1 regulates the activity of mechanosensitive kinases. Deletion of Jagged1 reduces the activity of VEGFR2 and ERK in vitro and diminished ERK activity in zebrafish embryos without affecting canonical Notch signaling. Furthermore, the direct physical stimulation of Jagged1 using antibody-conjugated beads triggers the activation of VEGFR2 and ERK, mediated by Jagged1-induces Src activation. Taken together, we demonstrate a novel non-canonical role for Jagged1 as a regulator of the activity of pathways involved in endothelial mechanotransduction.