{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:17:14Z","timestamp":1792016234558,"version":"4.4.0"},"reference-count":76,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,8]],"date-time":"2025-02-08T00:00:00Z","timestamp":1738972800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["51873168"],"award-info":[{"award-number":["51873168"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Huntington\u2019s disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. While traditionally viewed through the lens of neuronal dysfunction, emerging evidence highlights the critical role of endothelial dysfunction in HD pathogenesis. This review provides a comprehensive overview of endothelial dysfunction in HD, drawing on findings from both animal models and human studies. Key features of endothelial dysfunction in HD include impaired angiogenesis, altered cerebral blood flow, compromised neurovascular coupling and cerebrovascular reactivity, and increased blood\u2013brain barrier permeability. Genetic factors such as the mutant huntingtin protein, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1\u03b1), Brain-derived neurotrophic factor (BDNF), and the adenosine A2A receptor (ADORA2A) interact to influence endothelial function in complex ways. Various therapeutic approaches targeting endothelial dysfunction, including antioxidants, nitric oxide enhancers, calcium channel blockers, statins, and metformin, have shown promise in preclinical HD models but face translational challenges, particularly regarding optimal timing of intervention and patient stratification. The implications of these findings suggest that reconceptualizing HD as a neurovascular disorder, rather than purely neuronal, could lead to more effective treatment strategies. Future research priorities should include: (1) developing validated vascular biomarkers for disease progression, (2) advancing neuroimaging techniques to monitor endothelial dysfunction in real-time. These directions will be crucial for bridging the current gap between preclinical promise and clinical success in vascular-targeted HD therapeutics.<\/jats:p>","DOI":"10.3390\/ijms26041432","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T04:44:03Z","timestamp":1739162643000},"page":"1432","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Endothelial Dysfunction in Huntington\u2019s Disease: Pathophysiology and Therapeutic Implications"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4292-3395","authenticated-orcid":false,"given":"Ning","family":"Hu","sequence":"first","affiliation":[{"name":"School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of WUT-AMU, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Peng","sequence":"additional","affiliation":[{"name":"School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimeng","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9758-9870","authenticated-orcid":false,"given":"Kai","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, China"},{"name":"Hubei Key Laboratory of Nanomedicine for Neurodegenerative Diseases, Wuhan University of Technology, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taolei","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, China"},{"name":"Hubei Key Laboratory of Nanomedicine for Neurodegenerative Diseases, Wuhan University of Technology, Wuhan 430070, China"},{"name":"State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15005","DOI":"10.1038\/nrdp.2015.5","article-title":"Huntington disease","volume":"1","author":"Bates","year":"2015","journal-title":"Nat. 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