{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T20:39:18Z","timestamp":1790023158974,"version":"4.0.1"},"reference-count":62,"publisher":"American Society for Clinical Investigation","issue":"23","license":[{"start":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T00:00:00Z","timestamp":1575504000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Neurosciences Foundation and The Stroke Association","award":["TSA 2013\/02"],"award-info":[{"award-number":["TSA 2013\/02"]}]},{"name":"Medical Research Council","award":["MC-PC-15076,(MRC)"],"award-info":[{"award-number":["MC-PC-15076,(MRC)"]}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation;","doi-asserted-by":"crossref","award":["RE\/13\/5\/30177,(BHF)"],"award-info":[{"award-number":["RE\/13\/5\/30177,(BHF)"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,12,5]]},"abstract":"<jats:p>\n                    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) leads to premature stroke and vascular dementia. Mechanism-specific therapies for this aggressive cerebral small vessel disease are lacking. CADASIL is caused by\n                    <jats:italic>NOTCH3<\/jats:italic>\n                    mutations that influence vascular smooth muscle cell (VSMC) function through unknown processes. We investigated molecular mechanisms underlying the vasculopathy in CADASIL focusing on endoplasmic reticulum (ER) stress and RhoA\/Rho kinase (ROCK). Peripheral small arteries and VSMCs were isolated from gluteal biopsies of CADASIL patients and mesentery of TgNotch3\n                    <jats:sup>R169C<\/jats:sup>\n                    mice (CADASIL model). CADASIL vessels exhibited impaired vasorelaxation, blunted vasoconstriction, and hypertrophic remodeling. Expression of\n                    <jats:italic>NOTCH3<\/jats:italic>\n                    and ER stress target genes was amplified and ER stress response, Rho kinase activity, superoxide production, and cytoskeleton-associated protein phosphorylation were increased in CADASIL, processes associated with Nox5 upregulation. Aberrant vascular responses and signaling in CADASIL were ameliorated by inhibitors of Notch3 (\u03b3-secretase inhibitor), Nox5 (mellitin), ER stress (4-phenylbutyric acid), and ROCK (fasudil). Observations in human CADASIL were recapitulated in TgNotch3\n                    <jats:sup>R169C<\/jats:sup>\n                    mice. These findings indicate that vascular dysfunction in CADASIL involves ER stress\/ROCK interplay driven by Notch3-induced Nox5 activation and that\n                    <jats:italic>NOTCH3<\/jats:italic>\n                    mutation\u2013associated vascular pathology, typical in cerebral vessels, also manifests peripherally. We define Notch3-Nox5\/ER stress\/ROCK signaling as a putative mechanism-specific target and suggest that peripheral artery responses may be an accessible biomarker in CADASIL.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.131344","type":"journal-article","created":{"date-parts":[[2019,10,24]],"date-time":"2019-10-24T12:01:17Z","timestamp":1571918477000},"source":"Crossref","is-referenced-by-count":49,"title":["ER stress and Rho kinase activation underlie the vasculopathy of CADASIL"],"prefix":"10.1172","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5158-9263","authenticated-orcid":true,"given":"Karla B.","family":"Neves","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2845-4982","authenticated-orcid":true,"given":"Adam 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