Latrophilin mediates flow activation of Notch to control vascular endothelial phenotype and atherosclerosis

Fluid shear stress (FSS) is a major determinant of endothelial cell (EC) phenotype, with physiological laminar FSS promoting arterial identity and stability, whereas disturbed FSS promotes atherosclerosis. We previously identified the adhesion G protein-coupled receptor (GPCR) Latrophilin-2 (Lphn2) as a junctional protein required for FSS activation of the PECAM1/VE-cadherin/VEGFR2/PlexinD1 junctional mechanosensory pathway, which promotes EC inflammatory activation and atherogenesis in disturbed flow. We now report that Lphn2 endothelial cell specific knockout (ECKO) hyperlipidemic mice develop larger plaques than controls, opposite from PECAM-1 KO mice. Transcriptomic analysis revealed that Lphn2 contributes more than half of the flow-responsive gene expression program but suppresses proinflammatory pathways. The Notch pathway is activated by FSS at EC cell-cell junctions and promotes arterial identity and suppresses sprouting and inflammation. Lphn2 is essential for flow-induced activation of Notch1 but had no effect on activation by ligand. Lphn2 activated Notch independent of its GPCR function and associated with Notch1 and {ramshorn}-secretase in response to flow. Portions of the Lphn2-dependent genes were rescued by expression of the Notch1 intracellular domain (22%) and the transmembrane domain (30%), with both limiting inflammatory gene expression. Lphn2 is thus a critical mediator of FSS signaling through G protein-independent activation of Notch for suppressing vascular inflammation as well as G protein-dependent activation of the PECAM-1 pathway. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/662676v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@11e055forg.highwire.dtl.DTLVardef@1f2a5acorg.highwire.dtl.DTLVardef@15af06aorg.highwire.dtl.DTLVardef@15dd97d_HPS_FORMAT_FIGEXP M_FIG Latrophilin-Notch axis to suppress vascular inflammation C_FIG