2. Academic Validation
  3. Circulating extracellular vesicles from patients with traumatic brain injury induce cerebrovascular endothelial dysfunction

Circulating extracellular vesicles from patients with traumatic brain injury induce cerebrovascular endothelial dysfunction

  • Pharmacol Res. 2023 May 6;106791. doi: 10.1016/j.phrs.2023.106791.
Lei Li 1,  Fanjian Li 2,  Xuesong Bai 3,  Haoran Jia 2,  Cong Wang 2,  Peng Li 4,  Qiaoling Zhang 2,  Siyu Guan 2,  Ruilong Peng 2,  Shu Zhang 2,  Jing-Fei Dong 5,  Jianning Zhang 6,  Xin Xu 7
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China; Tianjin Neurological Institute; Department of Neurosurgery, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, China.
  • 2 Tianjin Neurological Institute; Department of Neurosurgery, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, China.
  • 3 Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China; China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, China.
  • 4 Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China; Department of Neurosurgery, Beijing Fengtai You'anmen Hospital, 199 You'anmen Outer Street, Beijing, China.
  • 5 Bloodworks Research Institute and Division of Hematology, Department of Medicine, University of Washington, School of Medicine, Seattle, WA, USA.
  • 6 Tianjin Neurological Institute; Department of Neurosurgery, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, China. Electronic address: [email protected].
  • 7 Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China; China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, China. Electronic address: [email protected].
PMID: 37156450 DOI: 10.1016/j.phrs.2023.106791
Abstract

Endothelial dysfunction is a key proponent of pathophysiological process of traumatic brain injury (TBI). We previously demonstrated that extracellular vesicles (EVs) released from injured brains led to endothelial barrier disruption and vascular leakage. However, the molecular mechanisms of this EV-induced endothelial dysfunction (endotheliopathy) remain unclear. Here, we enriched plasma EVs from TBI patients (TEVs), and detected high mobility group box 1 (HMGB1) exposure to 50.33 ± 10.17% of TEVs and the number of HMGB1+TEVs correlated with injury severity. We then investigated for the first time the impact of TEVs on endothelial function using adoptive transfer models. We found that TEVs induced dysfunction of cultured human umbilical vein endothelial cells and mediated endothelial dysfunction in both normal and TBI mice, which were propagated through the HMGB1-activated receptor for advanced glycation end products (RAGE)/Cathepsin B signaling, and the resultant NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and canonical Caspase-1/gasdermin D (GSDMD)-dependent Pyroptosis. Finally, von Willebrand factor (VWF) was detected on the surface of 77.01 ± 7.51% of HMGB1+TEVs. The TEV-mediated endotheliopathy was reversed by a polyclonal VWF antibody, indicating that VWF might serve a coupling factor that tethered TEVs to ECs, thus facilitating HMGB1-induced endotheliopathy. These results suggest that circulating EVs isolated from patients with TBI alone are sufficient to induce endothelial dysfunction and contribute to secondary brain injury that are dependent on immunologically active HMGB1 exposed on their surface. This finding provided new insight for the development of potential therapeutic targets and diagnostic biomarkers for TBI.

Keywords

Endothelial cell dysfunction; Extracellular vesicles, High mobility group box 1; Traumatic brain injury; von Willebrand factor.

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