Neuronal Endothelin a Receptor Mediates Experimental and Clinical Vascular Pain through an Endothelial‐Neural Axis

Vascular dysfunction causes vascular pain (VP), the most common clinical manifestation of prevalent vascular diseases, while the mechanisms remain elusive. Mouse models are developed by mimicking peripheral vascular diseases and combining multiple strategies to demonstrate that primary sensory neuronal endothelin A receptor (ETAR) mediates experimental and clinical VP through an endothelial-neural axis. Endothelial cells (ECs), but not macrophages or smooth muscle cells (SMCs), release endothelin-1 (ET-1) and directly activate primary sensory neurons by binding to ETAR on sensory neurons, resulting in VP. Mice that underwent vessel ligation exhibit long-lasting mechanical hyperalgesia, but no heat hyperalgesia or cold allodynia, without inflammatory cell infiltration into or gliosis in the nervous system. These mice also display a moderate decrease in blood perfusion in the affected hindpaws, without evident ischemic injury or tissue necrosis after vessel ligation. Activating ECs with optogenetics or chemogenetics elicits spontaneous pain-like behaviors and lasting mechanical hyperalgesia. Blocking the increased endothelial ET-1/neural ETAR signal reduces pain-like behaviors caused by vessel ligation or activation of ECs. Treatment with oral bosentan alleviates VP in clinical patients with tourniquet-induced VP. These findings suggest that targeting the endothelial-neural axis and ET-1/ETAR pathway may represent therapeutic strategies for VP.

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Journal
Advanced Science
Published
2025-08-14
DOI
https://doi.org/10.1002/advs.202512375
Citations
3
Primary Topic
Nitric Oxide and Endothelin Effects
Type
article
Field-Weighted Citation Impact
3.49
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article

Neuronal Endothelin a Receptor Mediates Experimental and Clinical Vascular Pain through an Endothelial‐Neural Axis

Ying-Ying Zhang, Ziyi Zhu, Zuojie Jiang, Changyu Jiang et al.
3 citations
Advanced Science
Nitric Oxide and Endothelin Effects
3.49
article

Neuronal Endothelin a Receptor Mediates Experimental and Clinical Vascular Pain through an Endothelial‐Neural Axis

Ying-Ying Zhang, Ziyi Zhu, Zuojie Jiang, Changyu Jiang, Yan-Gang Sun, Qingyi Li, Yong Chen, Peng-Bo Jing, Fenfei Gao, Feng Yu, Linnan Qian, Shiyu Sun, Bin Wu, Haili Pan, Haohao Chen, Lin Luo, Feng‐Ming Zhang, Bin Wang, Bing Wang, Tong Liu, Zhigang Lu, Jia-Yi Ge, Di Mu, Xiaomei Yang, Xing‐Jun Liu, Jie Wu, Zhuo Sun, Yu-Sen Ou, Su Liu
article en
3 citations

Abstract

Vascular dysfunction causes vascular pain (VP), the most common clinical manifestation of prevalent vascular diseases, while the mechanisms remain elusive. Mouse models are developed by mimicking peripheral vascular diseases and combining multiple strategies to demonstrate that primary sensory neuronal endothelin A receptor (ETAR) mediates experimental and clinical VP through an endothelial-neural axis. Endothelial cells (ECs), but not macrophages or smooth muscle cells (SMCs), release endothelin-1 (ET-1) and directly activate primary sensory neurons by binding to ETAR on sensory neurons, resulting in VP. Mice that underwent vessel ligation exhibit long-lasting mechanical hyperalgesia, but no heat hyperalgesia or cold allodynia, without inflammatory cell infiltration into or gliosis in the nervous system. These mice also display a moderate decrease in blood perfusion in the affected hindpaws, without evident ischemic injury or tissue necrosis after vessel ligation. Activating ECs with optogenetics or chemogenetics elicits spontaneous pain-like behaviors and lasting mechanical hyperalgesia. Blocking the increased endothelial ET-1/neural ETAR signal reduces pain-like behaviors caused by vessel ligation or activation of ECs. Treatment with oral bosentan alleviates VP in clinical patients with tourniquet-induced VP. These findings suggest that targeting the endothelial-neural axis and ET-1/ETAR pathway may represent therapeutic strategies for VP.

Advanced ScienceVol. 12(42)
Jiangnan University (CN), Nanjing University of Chinese Medicine (CN), Xuzhou Medical College (CN), Nantong University (CN), Shantou University (CN), Guangdong Polytechnic of Science and Technology (CN), Soochow University (CN), Center for Excellence in Brain Science and Intelligence Technology (CN), Shantou University Medical College (CN), Second Affiliated Hospital of Soochow University (CN), Shenzhen Municipal People's Government (CN)
Good health and well-being
Openalex Percentile: Top 7%
Nitric Oxide and Endothelin Effects
3.49
DOIOpen Access PDFOpenAlex
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