Sphingosine-1-phosphate cross-talks to Notch via a S1PR1-Dll4-MPDZ complex to regulate endothelial barrier function

Area of Science:

• Cardiovascular Biology
• Cell Signaling
• Endothelial Function

Background:

• Sphingosine-1-phosphate (S1P) is a bioactive lipid in high-density lipoproteins (HDL) that mediates cardiovascular benefits.
• S1P is known to enhance endothelial barrier integrity, but the underlying molecular mechanisms are not fully understood.

Purpose of the Study:

• To elucidate the novel signaling pathway by which S1P enhances endothelial barrier integrity.
• To investigate the role of Notch signaling in mediating S1P's effects on endothelial cells.

Main Methods:

• Utilized cell-based assays to study S1P-induced signaling.
• Investigated the interaction between S1P Receptor 1 (S1PR1), Delta-like protein 4 (Dll4), and MPDZ using co-immunoprecipitation and co-endocytosis assays.
• Assessed endothelial barrier function following genetic or pharmacological inhibition of key pathway components.

Main Results:

• Discovered that S1P activates Notch1, which is essential for enhancing Rac1 activity and adherens junction assembly, thereby improving endothelial barrier integrity.
• Identified a novel, G-protein-independent mechanism where S1P-bound S1PR1 complexes with Dll4 via MPDZ, leading to co-endocytosis and Notch activation.
• Demonstrated that loss or inhibition of Notch, Dll4, S1PR1, or MPDZ disrupts endothelial barrier function.

Conclusions:

• Elucidated a novel S1PR1-Dll4-MPDZ-Notch1 signaling axis coordinating S1P and Notch signaling.
• This pathway is critical for regulating endothelial cell signaling and maintaining barrier function.
• Findings provide new insights into the molecular basis of HDL's cardiovascular protective effects.