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Nus, Meritxell; Martínez-Poveda, Beatriz; MacGrogan, Donal; Chevre, Rafael; D'Amato, Gaetano; Sbroggio, Mauro; Rodríguez, Cristina; Martínez-González, José; Andrés, Vicente; Hidalgo, Andrés; Pompa, José Luis de la (2016): Endothelial Jag1-RBPJ signalling promotes inflammatory leucocyte recruitment and atherosclerosis. In: Cardiovascular Research, Vol. 112, No. 2: pp. 568-580
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Abstract

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 (RBPJ(flox/flox));Cadherin 5-CreERT, tamoxifen inducible driver mice (Cdh5-Cre(ERT))]. 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(-/-);RBPJ(flox/flox);Cdh5-Cre(ERT) 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-kappa B). This N1ICD-NF-kappa B 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.