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Endothelial Jag1-RBPJ signalling promotes inflammatory leucocyte recruitment and atherosclerosis

2016; Oxford University Press; Volume: 112; Issue: 2 Linguagem: Inglês

10.1093/cvr/cvw193

1755-3245

Meritxell Nus, Beatriz Martı́nez-Poveda, Donal MacGrogan, Rafael Chevre, Gaetano D’Amato, Mauro Sbroggió, Cristina Rodrı́guez, José Martı́nez-González, Vicente Andrés, Andrés Hidalgo, José Luis de la Pompa,

Angiogenesis and VEGF in Cancer

To determine the role of NOTCH during the arterial injury response and the subsequent chronic arterial-wall inflammation underlying atherosclerosis.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.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.