Extracellular vesicle-carried Jagged-1 inhibits HUVEC sprouting in a 3D microenvironment
NOTCH signalling is an evolutionarily conserved juxtacrine signalling pathway that is essential in development. Jagged1 (JAG1) and Delta-like ligand 4 (DLL4) are transmembrane NOTCH ligands that regulate angiogenesis by controlling endothelial cell (EC) differentiation, vascular development and maturation. In addition, DLL4 could bypass its canonical cell–cell contact-dependent signalling to influence NOTCH signalling and angiogenesis at a distance when it is packaged into extracellular vesicles (EVs). However, it is not clear whether JAG1 could also be packaged into EVs to influence NOTCH signalling and angiogenesis. In this work, we demonstrate that JAG1 is also packaged into EVs. We present evidence that JAG1-EVs inhibit NOTCH signalling and regulate EC behaviour and function. JAG1-EVs inhibited VEGF-induced HUVEC proliferation and migration in 2D culture condition and suppressed sprouting in a 3D microfluidic microenvironment. JAG1-EV treatment of HUVECs leads to a reduction of Notch1 intracellular domain (N1-ICD), and the proteasome and the intracellular domain of JAG1 (JAG1-ICD) are both required for this reduction to occur. These findings reveal a novel mechanism of JAG1 function in NOTCH signalling and ECs through EVs.
KeywordsExtracellular vesicles NOTCH signalling Jagged-1
- 20.Lötvall J, Hill AF, Hochberg F et al (2014) Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the international society for extracellular vesicles. J Extracell Vesicles 3:1–6. https://doi.org/10.3402/jev.v3.26913 CrossRefGoogle Scholar
- 23.Takeshita K, Satoh M, Ii M et al (2007) Critical role of endothelial Notch1 signaling in postnatal angiogenesis. Circ Res 100:70–78. https://doi.org/10.1161/01.RES.0000254788.47304.6e CrossRefPubMedGoogle Scholar