title: Endothelial Jag1-RBPJ signalling promotes inflammatory leucocyte recruitment and atherosclerosis.
abstract: OBJECTIVE
  To determine the role of NOTCH during the arterial injury response and the subsequent chronic arterial-wall inflammation underlying atherosclerosis.
  
  
  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.
authors: Intercellular Signalling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain.|Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, West Forvie Building, Forvie Site, Robinson Way, Cambridge CB2 0SZ, UK.
authors: Meritxell
authors: M
authors: Nus
authors: Intercellular Signalling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors: Beatriz
authors: B
authors: Martínez-Poveda
authors: Intercellular Signalling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors: Donal
authors: D
authors: MacGrogan
authors: Molecular and Genetic Cardiovascular Pathophysiology Laboratory, CNIC, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors: Rafael
authors: R
authors: Chevre
authors: Intercellular Signalling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors: Gaetano
authors: G
authors: D'Amato
authors: Intercellular Signalling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors: Mauro
authors: M
authors: Sbroggio
authors: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB Sant Pau. Sant Antoni María Claret 167, 08025 Barcelona, Spain.
authors: Cristina
authors: C
authors: Rodríguez
authors: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB Sant Pau. Sant Antoni María Claret 167, 08025 Barcelona, Spain.
authors: José
authors: J
authors: Martínez-González
authors: Molecular and Genetic Cardiovascular Pathophysiology Laboratory, CNIC, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors: Vicente
authors: V
authors: Andrés
authors: Imaging Cardiovascular Inflammation and the Immune Response Laboratory, CNIC, Melchor Fernández Almagro 3, 28029 Madrid, Spain.|Institute for Cardiovascular Prevention, Ludwig-Maximilians University, Pettenkoferstr. 9, 80336 Munich, Germany.
authors: Andrés
authors: A
authors: Hidalgo
authors: Intercellular Signalling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors: José Luis
authors: JL
authors: de la Pompa