Differential gene expression in multiple neurological, inflammatory and connective tissue pathways in a spontaneous model of human small vessel stroke

Bailey, E. L. , McBride, M. W. , Crawford, W., McClure, J. D. , Graham, D. , Dominiczak, A. F. , Sudlow, C. L.M., Smith, C. and Wardlaw, J. M. (2014) Differential gene expression in multiple neurological, inflammatory and connective tissue pathways in a spontaneous model of human small vessel stroke. Neuropathology and Applied Neurobiology, 40(7), pp. 855-872. (doi:10.1111/nan.12116)

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Publisher's URL: http://onlinelibrary.wiley.com/doi/10.1111/nan.12116/abstract;jsessionid=A4E59B0A409F3DDEEB8D29A2993D0246.f02t04

Abstract

Aims: 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-PCRand pathway analysis in two brain regions (frontal and midcoronal) 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 pre-dating 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McBride, Dr Martin and Bailey, Dr Emma and Dominiczak, Professor Anna and Graham, Dr Delyth and McClure, Dr John
Authors: Bailey, E. L., McBride, M. W., Crawford, W., McClure, J. D., Graham, D., Dominiczak, A. F., Sudlow, C. L.M., Smith, C., and Wardlaw, J. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Neuropathology and Applied Neurobiology
Publisher:Wiley
ISSN:0305-1846
ISSN (Online):1365-2990
Copyright Holders:Copyright © 2014 Wiley
First Published:First published in Neuropathology and Applied Neurobiology 2014
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
464051Genomics and proteomics of hypertension and its vascular complications: the pathwayomic strategies.Anna DominiczakBritish Heart Foundation (BHF)RG/07/005/23633RI CARDIOVASCULAR & MEDICAL SCIENCES
2393320BHF ChairAnna DominiczakBritish Heart Foundation (BHF)CH/1998001RI CARDIOVASCULAR & MEDICAL SCIENCES