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Endothelial cells, which form the innermost layer of blood vessels, have been found to exhibit divergent morphology and functional impairments in the peripheral circulation of individuals with DS. DS is also a strong risk factor for Alzheimer's disease\u2010related neuropathology. Recent evidence linking cerebral vasculature to Alzheimer's disease, along with established correlations between cardiovascular and cognitive functions, prompted us to investigate brain parenchymal microcirculation reactivity in a DS mouse model. We used brain parenchymal arterioles to investigate the impact of DS on endothelium\u2010dependent vasodilatation using the Dp16 mouse model coupled with\n ex vivo<\/jats:italic>\n pressure myography and\n in vivo<\/jats:italic>\n two\u2010photon laser\u2010scanning microscopy. Two age cohorts of mice, young and middle\u2010aged adults, were employed to test for age dependence, with the imminent development of Alzheimer's disease with age of individuals with DS in mind. Using pressure myography combined with pharmacological inhibitors, we examined two essential vasodilatory pathways in intracerebral arterioles \u2013 endothelial nitric oxide synthase and endothelium\u2010dependent hyperpolarization mediated by small\u2010 and intermediate\u2010conductance potassium channels. These pathways exhibited reduced constitutive activity in the DS model in both age groups. Consistent with these impairments, we measured higher levels of pressure\u2010induced constriction, also referred to as myogenic tone, in arterioles from the cortex of Dp16 mice seen both\n in vivo<\/jats:italic>\n and\n ex vivo<\/jats:italic>\n . Together, our findings demonstrate altered cerebrovascular functionality in DS and identify possible therapeutic targets for alleviating symptoms associated with DS.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Down syndrome is associated with cardiovascular diseases.<\/jats:p>\n <\/jats:list-item>\n \n Endothelium\u2010dependent hyperpolarization and nitric oxide synthase activity are reduced in Dp16 brain parenchymal arterioles.<\/jats:p>\n <\/jats:list-item>\n \n \n Parenchymal arteriole myogenic tone is elevated in Dp16 mice both\n ex vivo<\/jats:italic>\n and\n in vivo<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:list-item>\n \n Endothelial dysfunction is a therapeutic target in Down syndrome.<\/jats:p>\n <\/jats:list-item>\n \n Restoration of cerebral blood flow through vascular modulation may be beneficial.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp290174","type":"journal-article","created":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T03:12:48Z","timestamp":1769915568000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Intracerebral age\u2010independent reduction of endothelium\u2010dependent hyperpolarization and nitric oxide signalling in the Dp16 mouse model of Down syndrome"],"prefix":"10.1113","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5826-3442","authenticated-orcid":false,"given":"Abigail N.","family":"Russell","sequence":"first","affiliation":[{"name":"Department of Anesthesiology University of Colorado Anschutz Medical Campus Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9576-9458","authenticated-orcid":false,"given":"Danielle A.","family":"Jeffrey","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology University of Colorado Anschutz Medical Campus Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9958-6588","authenticated-orcid":false,"given":"Gregory","family":"Seedorf","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology University of Colorado Anschutz Medical Campus Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2856-8373","authenticated-orcid":false,"given":"Hong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology University of Colorado Anschutz Medical Campus Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2725-0205","authenticated-orcid":false,"given":"Kelly D.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Linda Crnic Institute for Down Syndrome University of Colorado Anschutz Medical Campus Aurora CO USA"},{"name":"Department of Pediatrics Section of Developmental Biology University of Colorado Anschutz Medical Campus Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4051-2516","authenticated-orcid":false,"given":"Huntington","family":"Potter","sequence":"additional","affiliation":[{"name":"Linda Crnic Institute for Down Syndrome University of Colorado Anschutz Medical Campus Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4241-8723","authenticated-orcid":false,"given":"Mingxia","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology University of Colorado Anschutz Medical Campus Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2541-9185","authenticated-orcid":false,"given":"Fabrice","family":"Dabertrand","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology University of Colorado Anschutz Medical Campus Aurora CO USA"},{"name":"Department of Pharmacology University of Colorado Anschutz Medical Campus Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,31]]},"reference":[{"issue":"3","key":"e_1_2_5_2_1","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1159\/000056997","article-title":"Ts65Dn \u2013 localization of the translocation breakpoint and trisomic gene content in a mouse model for Down syndrome","volume":"93","author":"Akeson E. 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