Acetylation of α-tubulin restores endothelial cell injury and blood-brain barrier disruption after intracerebral hemorrhage in mice

  • Exp Mol Med. 2025 May;57(5):1064-1077. doi: 10.1038/s12276-025-01454-9.
Xuejiao Lei  #  1 ,  Eryi Sun  #  2 ,  Xufang Ru  1 ,  Yulian Quan  1 ,  Xuezhu Chen  3 ,  Qian Zhang  4 ,  Yougling Lu  4 ,  Qianying Huang  4 ,  Yujie Chen  1 ,  Wenyan Li  1 ,  Hua Feng  5  6 ,  Yang Yang  7  8  9 ,  Rong Hu  10
Affiliations
  • 1. Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
  • 2. Department of Neurosurgery, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.
  • 3. Department of Pathology, Public Health Medical Center, Chongqing, China.
  • 4. Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
  • 5. Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China. [email protected].
  • 6. State Key Laboratory of Trauma and Chemical Poisoning, Chongqing, China. [email protected].
  • 7. Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China. [email protected].
  • 8. State Key Laboratory of Trauma and Chemical Poisoning, Chongqing, China. [email protected].
  • 9. Department of Neurosurgery, The 904th Hospital of PLA, Anhui Medical University, Wuxi, China. [email protected].
  • 10. Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China. [email protected].
  • # Contributed equally.
PMID: 40335634 DOI: 10.1038/s12276-025-01454-9
Abstract

Damage to endothelial cells (ECs) is a key factor in blood-brain barrier (BBB) disruption after intracerebral hemorrhage (ICH). While microtubules are essential for EC structure, their role in BBB injury remains unclear. Here we investigated the role of acetylated α-tubulin (α-Ac-Tub) in BBB integration after ICH. Using an autologous blood injection model in the striatum, we showed that the expression of α-Ac-Tub and MEC17, an α-tubulin acetyltransferase, significantly decreased along the vessels around the hematoma after ICH. Conditional MEC17 knockout in ECs further reduced α-Ac-Tub levels and exacerbated BBB leakage, brain edema, hematoma expansion, inflammation and motor dysfunction. Conversely, selective α-Ac-Tub upregulation in ECs via intravenous delivery of AAV-BI30-MEC17-GFP alleviated BBB dysfunction and improved motor recovery. Similarly, the HDAC6 Inhibitor tubastatin A enhanced α-Ac-Tub levels, mitigating BBB damage and neurological deficits. Mechanistically, α-Ac-Tub deficiency in ECs reduced tight junction proteins (ZO-1 and Claudin5) and increased F-actin stress fibers through RhoA activation. Together, our findings highlighted α-Ac-Tub as a therapeutic target for restoring BBB function and reducing brain injury after ICH.

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