2. Academic Validation
  3. Brain ischemia causes systemic Notch1 activity in endothelial cells to drive atherosclerosis

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

  • Immunity. 2024 Sep 10;57(9):2157-2172.e7. doi: 10.1016/j.immuni.2024.07.002.
Mingming Liu 1,  Danni Wang 1,  Caiyun Qi 1,  Ming Zou 1,  Jiawei Song 2,  Lili Li 1,  Hengchang Xie 1,  Honglei Ren 1,  Hongying Hao 1,  Guili Yang 1,  Zixiao Li 3,  Qiang Zhang 2,  Jie Zhou 4,  Ding Ai 5,  Qiang Liu 6
Affiliations

Affiliations

  • 1 Department of Neurology, Tianjin Neurological Institute, Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, International Joint Laboratory of Ocular Diseases, Ministry of Education, Haihe Laboratory of Cell Ecosystem, Laboratory of Post-Neuroinjury Neurorepair and Regeneration in Central Nervous System Tianjin & Ministry of Education, Tianjin Medical University General Hospital, Tianjin 300052, China.
  • 2 Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin 300052, China.
  • 3 China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China.
  • 4 Department of Immunology, Tianjin Institute of Immunology, Tianjin Medical University, Tianjin 300070, China. Electronic address: zhoujie@tmu.edu.cn.
  • 5 Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China. Electronic address: dingai@tmu.edu.cn.
  • 6 Department of Neurology, Tianjin Neurological Institute, Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, International Joint Laboratory of Ocular Diseases, Ministry of Education, Haihe Laboratory of Cell Ecosystem, Laboratory of Post-Neuroinjury Neurorepair and Regeneration in Central Nervous System Tianjin & Ministry of Education, Tianjin Medical University General Hospital, Tianjin 300052, China. Electronic address: qliu@tmu.edu.cn.
PMID: 39079536 DOI: 10.1016/j.immuni.2024.07.002
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.

Keywords

atherosclerosis; brain ischemia; endothelial cells; inflammation; stroke.

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