{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T02:45:00Z","timestamp":1772851500191,"version":"3.50.1"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:sec>\n            <jats:title>Background and Purpose\u2014<\/jats:title>\n            <jats:p>\n              Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an autosomal dominant small vessel disease caused by C-terminal frameshift mutations in the\n              <jats:italic>TREX1<\/jats:italic>\n              gene that encodes the major mammalian 3\u2032 to 5\u2032 DNA exonuclease. RVCL-S is characterized by vasculopathy, especially in densely vascularized organs, progressive retinopathy, cerebral microvascular disease, white matter lesions, and migraine, but the underlying mechanisms are unknown.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods\u2014<\/jats:title>\n            <jats:p>Homozygous transgenic RVCL-S knock-in mice expressing a truncated Trex1 (three prime repair exonuclease 1) protein (similar to what is seen in patients) and wild-type littermates, of various age groups, were subjected to (1) a survival analysis, (2) in vivo postocclusive reactive hyperemia and ex vivo Mulvany myograph studies to characterize the microvascular and macrovascular reactivity, and (3) experimental stroke after transient middle cerebral artery occlusion with neurological deficit assessment.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results\u2014<\/jats:title>\n            <jats:p>\n              The mutant mice show increased mortality starting at midlife (\n              <jats:italic>P<\/jats:italic>\n              =0.03 with hazard ratio, 3.14 [95% CI, 1.05\u20139.39]). The mutants also show a vascular phenotype as evidenced by attenuated postocclusive reactive hyperemia responses (across all age groups; F[1, 65]=5.7,\n              <jats:italic>P<\/jats:italic>\n              =0.02) and lower acetylcholine-induced relaxations in aortae (in 20- to 24-month-old mice; RVCL-S knock-in: E\n              <jats:sub>max<\/jats:sub>\n              : 37\u00b18% versus WT: E\n              <jats:sub>max<\/jats:sub>\n              : 65\u00b16%,\n              <jats:italic>P<\/jats:italic>\n              =0.01). A vascular phenotype is also suggested by the increased infarct volume seen in 12- to 14-month-old mutant mice at 24 hours after infarct onset (RVCL-S knock-in: 75.4\u00b12.7 mm\n              <jats:sup>3<\/jats:sup>\n              versus WT: 52.9\u00b15.6 mm\n              <jats:sup>3<\/jats:sup>\n              ,\n              <jats:italic>P<\/jats:italic>\n              =0.01).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>Homozygous RVCL-S knock-in mice show increased mortality, signs of abnormal vascular function, and increased sensitivity to experimental stroke and can be instrumental to investigate the pathology seen in patients with RVCL-S.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.119.025176","type":"journal-article","created":{"date-parts":[[2019,12,6]],"date-time":"2019-12-06T10:00:19Z","timestamp":1575626419000},"page":"300-307","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["Increased Mortality and Vascular Phenotype in a Knock-In Mouse Model of Retinal Vasculopathy With Cerebral Leukoencephalopathy and Systemic Manifestations"],"prefix":"10.1161","volume":"51","author":[{"given":"Inge A.","family":"Mulder","sequence":"first","affiliation":[{"name":"From the Department of Neurology (I.A.M., G.M.T., M.J.H.W., A.M.J.M.v.d.M.), Leiden University Medical Center, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elo\u00edsa","family":"Rubio-Beltran","sequence":"additional","affiliation":[{"name":"Divison of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (E.R.-B., K.I., A.M.V.D.B.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khatera","family":"Ibrahimi","sequence":"additional","affiliation":[{"name":"Divison of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (E.R.-B., K.I., A.M.V.D.B.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oleh","family":"Dzyubachyk","sequence":"additional","affiliation":[{"name":"Division of Image Processing (LKEB), Department of Radiology (O.D., A.K.), Leiden University Medical Center, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Artem","family":"Khmelinskii","sequence":"additional","affiliation":[{"name":"Division of Image Processing (LKEB), Department of Radiology (O.D., A.K.), Leiden University Medical Center, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathias","family":"Hoehn","sequence":"additional","affiliation":[{"name":"In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Cologne, Germany (M.H.)"},{"name":"Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Juelich, Germany (M.H.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gisela M.","family":"Terwindt","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (I.A.M., G.M.T., M.J.H.W., A.M.J.M.v.d.M.), Leiden University Medical Center, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marieke J.H.","family":"Wermer","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (I.A.M., G.M.T., M.J.H.W., A.M.J.M.v.d.M.), Leiden University Medical Center, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoinette","family":"MaassenVanDenBrink","sequence":"additional","affiliation":[{"name":"Divison of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (E.R.-B., K.I., A.M.V.D.B.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arn M.J.M","family":"van den Maagdenberg","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (I.A.M., G.M.T., M.J.H.W., A.M.J.M.v.d.M.), Leiden University Medical Center, the Netherlands"},{"name":"Department of Human Genetics (A.M.J.M.v.d.M.), Leiden University Medical Center, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng2082"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M010051200"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.117.018556"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000006119"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aww217"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/121.2.303"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/1440-1681.12413"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.07.022"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.110.165993"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.str.20.1.84"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.3389\/fninf.2017.00003"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.WCB.0000046146.31247.A1"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2004.11.001"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.045096"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.3791\/4374"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2018.01.004"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01085.2012"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.73.1.147"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0703555"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1994.266.3.H952"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4610.2006.00596.x"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.str.31.8.1965"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2009.5"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.WCB.0000071883.63724.A7"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-006-0164-7"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1159\/000066505"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0026288"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.113.002944"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000048894.99865.02"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2009.07.002"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.2174\/156720210792231813"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2014.01.012"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2017.03.001"}],"container-title":["Stroke"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/STROKEAHA.119.025176","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T15:25:14Z","timestamp":1715613914000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/STROKEAHA.119.025176"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,1]]}},"alternative-id":["10.1161\/STROKEAHA.119.025176"],"URL":"https:\/\/doi.org\/10.1161\/strokeaha.119.025176","relation":{},"ISSN":["0039-2499","1524-4628"],"issn-type":[{"value":"0039-2499","type":"print"},{"value":"1524-4628","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1]]},"assertion":[{"value":"2018-09-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-10-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-12-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}