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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\u2010neural axis. Endothelial cells (ECs), but not macrophages or smooth muscle cells (SMCs), release endothelin\u20101 (ET\u20101) and directly activate primary sensory neurons by binding to ETAR on sensory neurons, resulting in VP. Mice that underwent vessel ligation exhibit long\u2010lasting 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\u2010like behaviors and lasting mechanical hyperalgesia. Blocking the increased endothelial ET\u20101\/neural ETAR signal reduces pain\u2010like behaviors caused by vessel ligation or activation of ECs. Treatment with oral bosentan alleviates VP in clinical patients with tourniquet\u2010induced VP. These findings suggest that targeting the endothelial\u2010neural axis and ET\u20101\/ETAR pathway may represent therapeutic strategies for VP.<\/jats:p>","DOI":"10.1002\/advs.202512375","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T13:41:59Z","timestamp":1755178919000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Neuronal Endothelin a Receptor Mediates Experimental and Clinical Vascular Pain through an Endothelial\u2010Neural Axis"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2602-7565","authenticated-orcid":false,"given":"Zuo\u2010Jie","family":"Jiang","sequence":"first","affiliation":[{"name":"School of Pharmacy Nantong University  Nantong Jiangsu Province 226019 China"},{"name":"Pain and Related Disease Research Laboratory Shantou University Medical College  Shantou Guangdong Province 515041 China"},{"name":"Department of 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