{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T08:40:00Z","timestamp":1792485600788,"version":"4.5.0"},"reference-count":35,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2016,2,10]],"date-time":"2016-02-10T00:00:00Z","timestamp":1455062400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"National Research Agency, France","award":["2009-RAE09011HSA"],"award-info":[{"award-number":["2009-RAE09011HSA"]}]},{"name":"National Research Agency, France","award":["2010-RPV11011HHA"],"award-info":[{"award-number":["2010-RPV11011HHA"]}]},{"name":"NIH","award":["R37DK053832"],"award-info":[{"award-number":["R37DK053832"]}]},{"name":"NIH","award":["P01HL095488"],"award-info":[{"award-number":["P01HL095488"]}]},{"name":"NIH","award":["R01HL121706"],"award-info":[{"award-number":["R01HL121706"]}]},{"name":"Totman Medical Research Trust"},{"DOI":"10.13039\/501100001674","name":"Leducq Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001677","name":"National Institute of Health and Medical Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2016,3]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      CADASIL is a genetic paradigm of cerebral small vessel disease caused by NOTCH3 mutations that stereotypically lead to the extracellular deposition of NOTCH3 ectodomain (Notch3\n                      <jats:sup>ECD<\/jats:sup>\n                      ) on the vessels. TIMP3 and vitronectin are 2 extracellular matrix proteins that abnormally accumulate in Notch3\n                      <jats:sup>ECD<\/jats:sup>\n                      \u2010containing deposits on brain vessels of mice and patients with CADASIL. Herein, we investigated whether increased levels of TIMP3 and vitronectin are responsible for aspects of CADASIL disease phenotypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Timp3<\/jats:italic>\n                      and\n                      <jats:italic>vitronectin<\/jats:italic>\n                      expression were genetically reduced in\n                      <jats:italic>TgNotch3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>R169C<\/jats:italic>\n                      <\/jats:sup>\n                      mice, a well\u2010established preclinical model of CADASIL. A mouse overexpressing human TIMP3 (\n                      <jats:italic>TgBAC\u2010TIMP3<\/jats:italic>\n                      ) was developed. Disease\u2010related phenotypes, including cerebral blood flow (CBF) deficits, white matter lesions, and Notch3\n                      <jats:sup>ECD<\/jats:sup>\n                      deposition, were evaluated between 6 and 20 months of age.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CBF responses to neural activity (functional hyperemia), topical application of vasodilators, and decreases in blood pressure (CBF autoregulation) were similarly reduced in\n                      <jats:italic>TgNotch3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>R169C<\/jats:italic>\n                      <\/jats:sup>\n                      and\n                      <jats:italic>TgBAC\u2010TIMP3<\/jats:italic>\n                      mice, and myogenic responses of brain arteries were likewise attenuated. These defects were rescued in\n                      <jats:italic>TgNotch3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>R169C<\/jats:italic>\n                      <\/jats:sup>\n                      mice by haploinsufficiency of\n                      <jats:italic>Timp3<\/jats:italic>\n                      , although the number of white matter lesions was unaffected. In contrast, haploinsufficiency or loss of\n                      <jats:italic>vitronectin<\/jats:italic>\n                      in\n                      <jats:italic>TgNotch3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>R169C<\/jats:italic>\n                      <\/jats:sup>\n                      mice ameliorated white matter lesions, although CBF responses were unchanged. Amelioration of cerebrovascular reactivity or white matter lesions in these mice was not associated with reduced Notch3\n                      <jats:sup>ECD<\/jats:sup>\n                      deposition in brain vessels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Elevated levels of TIMP3 and vitronectin, acting downstream of Notch3\n                      <jats:sup>ECD<\/jats:sup>\n                      deposition, play a role in CADASIL, producing divergent influences on early CBF deficits and later white matter lesions. ANN NEUROL 2016;79:387\u2013403\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.24573","type":"journal-article","created":{"date-parts":[[2015,12,9]],"date-time":"2015-12-09T13:00:53Z","timestamp":1449666053000},"page":"387-403","source":"Crossref","is-referenced-by-count":92,"title":["Reducing\n                    <scp>T<\/scp>\n                    imp3 or vitronectin ameliorates disease manifestations in\n                    <scp>CADASIL<\/scp>\n                    mice"],"prefix":"10.1002","volume":"79","author":[{"given":"Carmen","family":"Capone","sequence":"first","affiliation":[{"name":"Genetics and Pathogenesis of Cerebrovascular Diseases Inserm, U1161 and Univ Paris Diderot, Sorbonne Paris Cit\u00e9, UMRS 1161, F\u201075010 Paris France"},{"name":"DHU NeuroVasc, Sorbonne Paris Cit\u00e9 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Cognat","sequence":"additional","affiliation":[{"name":"Genetics and Pathogenesis of Cerebrovascular Diseases Inserm, U1161 and Univ Paris Diderot, Sorbonne Paris Cit\u00e9, UMRS 1161, F\u201075010 Paris France"},{"name":"DHU NeuroVasc, Sorbonne Paris Cit\u00e9 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamia","family":"Ghezali","sequence":"additional","affiliation":[{"name":"Genetics and Pathogenesis of Cerebrovascular Diseases Inserm, U1161 and Univ Paris Diderot, Sorbonne Paris Cit\u00e9, UMRS 1161, F\u201075010 Paris France"},{"name":"DHU NeuroVasc, Sorbonne Paris Cit\u00e9 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Baron\u2010Menguy","sequence":"additional","affiliation":[{"name":"Genetics and Pathogenesis of Cerebrovascular Diseases Inserm, U1161 and Univ Paris Diderot, Sorbonne Paris Cit\u00e9, 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