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The aetiology and pathogenesis of <jats:styled-content style=\"fixed-case\">SVD<\/jats:styled-content> are unknown, but largely attributed to hypertension or microatheroma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used the spontaneously hypertensive stroke\u2010prone rat (<jats:styled-content style=\"fixed-case\">SHRSP<\/jats:styled-content>), the closest spontaneous experimental model of human <jats:styled-content style=\"fixed-case\">SVD<\/jats:styled-content>, and age\u2010matched control rats kept under identical, non\u2010salt\u2010loaded conditions, to perform a blinded analysis of <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> microarray, <jats:styled-content style=\"fixed-case\">qRT<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content> and pathway analysis in two brain regions (frontal and mid\u2010coronal) commonly affected by <jats:styled-content style=\"fixed-case\">SVD<\/jats:styled-content> in the <jats:styled-content style=\"fixed-case\">SHRSP<\/jats:styled-content> at age five, 16 and 21 weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found gene expression abnormalities, with fold changes ranging from 2.5 to 59 for the 10 most differentially expressed genes, related to endothelial tight junctions (reduced), nitric oxide bioavailability (reduced), myelination (impaired), glial and microglial activity (increased), matrix proteins (impaired), vascular reactivity (impaired) and albumin (reduced), consistent with protein expression defects in the same rats. All were present at age 5 weeks thus predating blood pressure elevation. \u2018Neurological\u2019 and \u2018inflammatory\u2019 pathways were more affected than \u2018vascular\u2019 functional pathways.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This set of defects, although individually modest, when acting in combination could explain the <jats:styled-content style=\"fixed-case\">SHRSP's<\/jats:styled-content> susceptibility to microvascular and brain injury, compared with control rats. Similar combined, individually modest, but multiple neurovascular unit defects, could explain susceptibility to spontaneous human <jats:styled-content style=\"fixed-case\">SVD<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12116","type":"journal-article","created":{"date-parts":[[2014,1,13]],"date-time":"2014-01-13T07:21:55Z","timestamp":1389597715000},"page":"855-872","source":"Crossref","is-referenced-by-count":31,"title":["Differential gene expression in multiple neurological, inflammatory and connective tissue pathways in a spontaneous model of human small vessel stroke"],"prefix":"10.1111","volume":"40","author":[{"given":"Emma L.","family":"Bailey","sequence":"first","affiliation":[{"name":"Centre for Clinical Brain Sciences University of Edinburgh, Western General Hospital  Edinburgh"},{"name":"Department of Bioengineering Imperial College London  London"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin 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Sciences University of Glasgow  Glasgow"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cathie L.M.","family":"Sudlow","sequence":"additional","affiliation":[{"name":"Centre for Clinical Brain Sciences University of Edinburgh, Western General Hospital  Edinburgh"},{"name":"Centre for Molecular Medicine Institute of Genetics and Molecular Medicine University of Edinburgh, Western General Hospital  Edinburgh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin","family":"Smith","sequence":"additional","affiliation":[{"name":"Academic Department of Neuropathology Centre for Clinical Brain Sciences University of Edinburgh  Edinburgh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanna M.","family":"Wardlaw","sequence":"additional","affiliation":[{"name":"Centre for Clinical Brain Sciences University of Edinburgh, Western General Hospital  Edinburgh"},{"name":"SINAPSE Collaboration (Scottish Imaging Network, A Platform for Scientific 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