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Using in vivo two-photon microscopy in R6\/2 HD-model mice, we reveal a striking divergence in barrier dysfunction. Surface vessels of the blood-cerebrospinal fluid barrier (BCSFB) drive pathology\u00a0in HD by paracellular leakage, while parenchymal vessels forming the blood-brain barrier (BBB) exhibit increased vesicular transport and adsorptive-mediated transcytosis (AMT), with arterioles representing the most critically impacted vascular segment. The pathology of both barriers was spatially-matched with astrocyte activation pattern\u00a0localized to affected vessels\u00a0both in R6\/2 mice\u00a0and in\u00a0brains of HD patients. Sphingosine-1-phosphate receptor 1 (S1pr1) agonist treatment reversed BCSFB leakage and partially restored BBB function, selectively reducing AMT in arterioles, with no effect in capillaries and venules. These findings redefine HD vascular pathology, demonstrating heterogeneous, vessel-type-specific barrier failure beyond generalized \u201cdisruption,\u201d uncovering mechanistic vulnerabilities and the therapeutic potential of S1pr1 modulation.<\/jats:p>","DOI":"10.1038\/s41467-026-77474-4","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T15:04:21Z","timestamp":1789225461000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Huntington\u2019s disease vasculopathy is barrier-type-selective and arteriolar-dominant with spatially-coupled astrogliosis and reversible by S1pr1 stimulation"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6852-5300","authenticated-orcid":false,"given":"Krzysztof","family":"Kucharz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana","family":"Soylu-Kucharz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2544-5562","authenticated-orcid":false,"given":"Martine","family":"Saint-Pierre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2782-5454","authenticated-orcid":false,"given":"Melanie","family":"Alpaugh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippa Liliendahl","family":"Qvist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Bj\u00f6rkqvist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7027-7193","authenticated-orcid":false,"given":"Niels Henning","family":"Skotte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5490-1961","authenticated-orcid":false,"given":"Francesca","family":"Cicchetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1517-1131","authenticated-orcid":false,"given":"Martin Johannes","family":"Lauritzen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"77474_CR1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1083\/jcb.201412147","volume":"209","author":"S Tietz","year":"2015","unstructured":"Tietz, S. & Engelhardt, B. 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