title: Differential gene expression in multiple neurological, inflammatory and connective tissue pathways in a spontaneous model of human small vessel stroke.
abstract: OBJECTIVE
  Cerebral small vessel disease (SVD) causes a fifth of all strokes plus diffuse brain damage leading to cognitive decline, physical disabilities and dementia. The aetiology and pathogenesis of SVD are unknown, but largely attributed to hypertension or microatheroma.
  
  
  METHODS
  We used the spontaneously hypertensive stroke-prone rat (SHRSP), the closest spontaneous experimental model of human SVD, and age-matched control rats kept under identical, non-salt-loaded conditions, to perform a blinded analysis of mRNA microarray, qRT-PCR and pathway analysis in two brain regions (frontal and mid-coronal) commonly affected by SVD in the SHRSP at age five, 16 and 21 weeks.
  
  
  RESULTS
  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. 'Neurological' and 'inflammatory' pathways were more affected than 'vascular' functional pathways.
  
  
  CONCLUSIONS
  This set of defects, although individually modest, when acting in combination could explain the SHRSP's 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 SVD.
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, Edinburgh; Department of Bioengineering, Imperial College London, London.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Bailey
authors.forename: Martin W
authors.initials: MW
authors.lastname: McBride
authors.forename: Wendy
authors.initials: W
authors.lastname: Beattie
authors.forename: John D
authors.initials: JD
authors.lastname: McClure
authors.forename: Delyth
authors.initials: D
authors.lastname: Graham
authors.forename: Anna F
authors.initials: AF
authors.lastname: Dominiczak
authors.forename: Cathie L M
authors.initials: CL
authors.lastname: Sudlow
authors.forename: Colin
authors.initials: C
authors.lastname: Smith
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wardlaw
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D059345:Cerebral Small Vessel Diseases / Q000150:complications* / Q000235:genetics*; D003238:Connective Tissue / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000150:complications / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D008297:Male; D009422:Nervous System Diseases / Q000150:complications / Q000235:genetics; D040081:Protein Array Analysis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D012333:RNA, Messenger
keywords: blood brain barrier; lacunar stroke; neurovascular unit; small vessel disease; stroke