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Matilda Ziegler Foundation for the Blind","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010310","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001717","name":"Karl Kirchgessner Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001717","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["P30EY003790"],"award-info":[{"award-number":["P30EY003790"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,8,7]]},"abstract":"<jats:p>Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological syndrome characterized by small vessel disease (SVD), stroke, and vascular cognitive impairment and dementia caused by mutations in NOTCH3. No therapies are available for this condition. Loss of mural cells, which encompass pericytes and vascular smooth muscle cells, is a hallmark of CADASIL and other SVDs, including diabetic retinopathy, resulting in vascular instability. Here, we showed that Notch3 signaling is both necessary and sufficient to support mural cell coverage in arteries using genetic rescue in Notch3 knockout mice. Furthermore, we show that systemic administration of an agonist Notch3 antibody prevents mural cell loss and modifies plasma proteins associated with Notch3 activity, including endostatin\/collagen 18\u03b11 and Notch3 extracellular domain in mice with the C455R mutation, a CADASIL variant associated with Notch3 loss of function. These findings open opportunities for the treatment of CADASIL and other SVDs by modulating Notch3 signaling.<\/jats:p>","DOI":"10.1084\/jem.20161715","type":"journal-article","created":{"date-parts":[[2017,7,11]],"date-time":"2017-07-11T15:41:07Z","timestamp":1499787667000},"page":"2271-2282","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":66,"title":["Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL"],"prefix":"10.1084","volume":"214","author":[{"given":"Arturo I.","family":"Machuca-Parra","sequence":"first","affiliation":[{"name":"Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander A.","family":"Bigger-Allen","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angie V.","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6408-4555","authenticated-orcid":true,"given":"Anissa","family":"Boutabla","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 1"},{"name":"Grenoble Alpes University, Grenoble, France 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4382-9391","authenticated-orcid":true,"given":"Jonathan","family":"Cardona-V\u00e9lez","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 1"},{"name":"Universidad Pontificia Bolivariana, Medell\u00edn, Colombia 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0678-768X","authenticated-orcid":true,"given":"Dhanesh","family":"Amarnani","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magali","family":"Saint-Geniez","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4333-3756","authenticated-orcid":true,"given":"Christian W.","family":"Siebel","sequence":"additional","affiliation":[{"name":"Department of Discovery Oncology, Genentech, Inc., South San Francisco, CA 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9106-6416","authenticated-orcid":true,"given":"Leo A.","family":"Kim","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9652-8974","authenticated-orcid":true,"given":"Patricia A.","family":"D\u2019Amore","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 1"},{"name":"Department of Pathology, Harvard Medical School, Boston, MA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3192-9117","authenticated-orcid":true,"given":"Joseph F.","family":"Arboleda-Velasquez","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2017,7,11]]},"reference":[{"key":"2023073009532688100_bib1","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1212\/WNL.59.2.277","article-title":"C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke","volume":"59","author":"Arboleda-Velasquez","year":"2002","journal-title":"Neurology."},{"key":"2023073009532688100_bib2","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1093\/hmg\/ddi171","article-title":"CADASIL mutations impair Notch3 glycosylation by Fringe","volume":"14","author":"Arboleda-Velasquez","year":"2005","journal-title":"Hum. 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