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

SiJing Liao^1,2Fei-Ran Zhou²Qun Li²Tao Jin³Gui-Fang Xiang⁴Xin Wang²Yan Liu²HQ ZHU²Qing Liu^2,4*Yuexin Liu^5*Ying Zhang^2*

• 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

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.