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ORIGINAL RESEARCH article

Front. Mol. Neurosci.

Sec. Pain Mechanisms and Modulators

Volume 18 - 2025 | doi: 10.3389/fnmol.2025.1603619

Endoglin alleviates neuropathic pain by protecting blood-spinal cord barrier through TGF-β/Smad2 signaling pathway

Provisionally accepted
SiJing  LiaoSiJing Liao1,2Fei-Ran  ZhouFei-Ran Zhou2Qun  LiQun Li2Tao  JinTao Jin3Gui-Fang  XiangGui-Fang Xiang4Xin  WangXin Wang2Yan  LiuYan Liu2HQ  ZHUHQ ZHU2Qing  LiuQing Liu2,4*Yuexin  LiuYuexin Liu5*Ying  ZhangYing Zhang2*
  • 1The Affiliated Hospital of Southwest Medical University, Luzhou, China
  • 2Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
  • 3Suining First People's Hospital, Suining, Sichuan Province, China
  • 4Hejiang County Traditional Chinese Medicine Hospital, Luzhou, Sichuan Province, China
  • 5Zhongshan Hospital, Fudan University, Shanghai, Shanghai Municipality, China

The final, formatted version of the article will be published soon.

Central neuroinflammation has been considered as a pivotal factor in the pathogenesis of neuropathic pain. The blood-spinal cord barrier (BSCB) is a structural entity that functions to prevent the leakage of nociceptive mediators and inflammatory factors into the spinal cord. Dysfunction of the BSCB leads to central neuroinflammation, even neuropathic pain. However, the molecular mechanisms of BSCB dysfunction mediating neuropathic pain are not well understood. In a clinical study, we found that patients diagnosed with postherpetic neuralgia (PHN), a type of neuropathic pain, exhibited lower blood endoglin levels compared to healthy subjects. In animal studies, we also observed a significant reduction in endoglin expression of spared nerve injury(SNI)rats compared to sham-operated controls. Furthermore, recombinant endoglin protein effectively alleviated mechanical and thermal hyperalgesia in SNI rats and significantly reversed SNI-induced microglial activation, inflammation, BSCB permeability impairment and phosphorylation of NR2B at Tyr1472 in the spinal cord. Notably, we found that SNI induced a significant decrease in TGF β RI expression and Smad2 phosphorylation in the spinal cord. These findings suggest that reduction of endoglin expression disrupts the structural integrity and function of the BSCB through inhibition of the TGF-β /Smad2 signaling pathway in endothelial cells, thereby leading to microglial activation, inflammation, NR2B phosphorylation in spinal cord neurons, and mechanical and thermal hyperalgesia. Our study elucidates a key mechanism underlying the pathogenesis of neuropathic pain and highlights endoglin as a potential therapeutic target for its treatment.

Keywords: endoglin, TGF-β/Smad2, neuropathic pain, blood-spinal cord barrier, endothelial cell

Received: 31 Mar 2025; Accepted: 04 Aug 2025.

Copyright: © 2025 Liao, Zhou, Li, Jin, Xiang, Wang, Liu, ZHU, Liu, Liu and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Qing Liu, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
Yuexin Liu, Zhongshan Hospital, Fudan University, Shanghai, 200032, Shanghai Municipality, China
Ying Zhang, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China

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