Brain ischemia causes systemic Notch1 activity in endothelial cells to drive atherosclerosis.

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 9432918 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4180 (Electronic) Linking ISSN: 10747613 NLM ISO Abbreviation: Immunity Subsets: MEDLINE
    • Publication Information:
      Publication: Cambridge, MA : Cell Press
      Original Publication: Cambridge, Mass. : Cell Press, c1994-
    • Subject Terms:
      Atherosclerosis*/metabolism ; Atherosclerosis*/immunology ; Brain Ischemia*/metabolism ; Calcium-Binding Proteins*/metabolism ; Endothelial Cells*/metabolism ; Receptor, Notch1*/metabolism; Animals ; Humans ; Male ; Mice ; Cell Adhesion ; Cellular Senescence ; Jagged-1 Protein/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Signal Transduction ; Stroke/metabolism ; Stroke/immunology ; Vascular Cell Adhesion Molecule-1/metabolism
    • Abstract:
      Stroke leads to persistently high risk for recurrent vascular events caused by systemic atheroprogression that is driven by endothelial cell (EC) activation. However, whether and how stroke induces sustained pro-inflammatory and proatherogenic endothelial alterations in systemic vessels remain poorly understood. We showed that brain ischemia induces persistent activation, the upregulation of adhesion molecule VCAM1, and increased senescence in peripheral ECs until 4 weeks after stroke onset. This aberrant EC activity resulted from sustained Notch1 signaling, which was triggered by increased circulating Notch1 ligands DLL1 and Jagged1 after stroke in mice and humans. Consequently, this led to increased myeloid cell adhesion and atheroprogression by generating a senescent, pro-inflammatory endothelium. Notch1- or VCAM1-blocking antibodies and the genetic ablation of endothelial Notch1 reduced atheroprogression after stroke. Our findings revealed a systemic machinery that induces the persistent activation of peripheral ECs after stroke, which paves the way for therapeutic interventions or the prevention of recurrent vascular events following stroke.
      Competing Interests: Declaration of interests The authors declare no competing interests.
      (Copyright © 2024 Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: atherosclerosis; brain ischemia; endothelial cells; inflammation; stroke
    • Accession Number:
      0 (Calcium-Binding Proteins)
      0 (Dlk1 protein, mouse)
      0 (Jagged-1 Protein)
      0 (Notch1 protein, mouse)
      0 (Receptor, Notch1)
      0 (Vascular Cell Adhesion Molecule-1)
    • Publication Date:
      Date Created: 20240730 Date Completed: 20240911 Latest Revision: 20240919
    • Publication Date:
      20240919
    • Accession Number:
      10.1016/j.immuni.2024.07.002
    • Accession Number:
      39079536