Neuronal Endothelin a Receptor Mediates Experimental and Clinical Vascular Pain through an Endothelial‐Neural Axis
Source abstract
Abstract
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.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Nitric Oxide and Endothelin Effects · Neuropeptides and Animal Physiology · Eicosanoids and Hypertension Pharmacology
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
School of Pharmacy Nantong University Nantong Jiangsu Province 226019 China
Pain and Related Disease Research Laboratory Shantou University Medical College Shantou Guangdong Province 515041 China
Department of Pharmacology Shantou University Medical College Shantou Guangdong Province 515041 China
Guangdong Institute of Intelligence Science and Technology Zhuhai Guangdong Province 519031 China
Department of Anesthesiology The Affiliated Hospital of Xuzhou Medical University Xuzhou Jiangsu Province 221000 China
Institute of Pain Medicine and Special Environmental Medicine Nantong University Nantong Jiangsu Province 226019 China
Xuzhou Medical University Xuzhou Jiangsu Province 221004 China
School of Integrative Medicine Nanjing University of Chinese Medicine Nanjing Jiangsu Province 210023 China
School of Design Jiangnan University Wuxi Jiangsu Province 214122 China
Department of Rheumatology and Immunology The Fourth Affiliated Hospital of Soochow University Suzhou Jiangsu Province 215004 China
Department of Pain Medicine Shenzhen Municipal Key Laboratory for Pain Medicine The Affiliated Nanshan Hospital of Shenzhen University Shenzhen Guangdong Province 518000 China
Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Science Shanghai 200031 China
Funding
National Natural Science Foundation of China · Jiangsu Provincial Medical Youth Talent
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