Endothelial Jag1-RBPJ signalling promotes inflammatory leucocyte recruitment and atherosclerosis.

Aim To determine the role of NOTCH during the arterial injury response and the subsequent chronic arterial-wall inflammation underlying atherosclerosis. Methods and results We have generated a mouse model of endothelial-specific ( Cdh5 -driven) depletion of the Notch effector recombination signal binding protein for immunoglobulin kappa J region (RBPJ) [( ApoE −/−); homozygous RBPJk conditional mice ( RBPJflox/flox ); Cadherin 5-CreERT, tamoxifen inducible driver mice ( Cdh5-CreERT )]. Endothelial-specific deletion of RBPJ or systemic deletion of Notch1 in athero-susceptible ApoE−/− mice fed a high-cholesterol diet for 6 weeks resulted in reduced atherosclerosis in the aortic arch and sinus. Intravital microscopy revealed decreased leucocyte rolling on the endothelium of ApoE−/− ; RBPJflox/flox ; Cdh5-CreERT mice, correlating with a lowered content of leucocytes and macrophages in the vascular wall. Transcriptome analysis revealed down-regulation of proinflammatory and endothelial activation pathways in atherosclerotic tissue of RBPJ- mutant mice. During normal Notch activation, Jagged1 signalling up-regulation in endothelial cells promotes nuclear translocation of the Notch1 intracellular domain (N1ICD) and its physical interaction with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). This N1ICD–NF-κB interaction is required for reciprocal transactivation of target genes, including vascular cell adhesion molecule-1 . Conclusions Notch signalling pathway inactivation decreases leucocyte rolling, thereby preventing endothelial dysfunction and vascular inflammation. Attenuation of Notch signalling might provide a treatment strategy for atherosclerosis.