These authors contributed equally to this work as junior.
Differential gene expression in multiple neurological, inflammatory and connective tissue pathways in a spontaneous model of human small vessel stroke
Article first published online: 17 NOV 2014
© 2014 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Neuropathology and Applied Neurobiology
Volume 40, Issue 7, pages 855–872, December 2014
How to Cite
Bailey, E. L., McBride, M. W., Beattie, 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: 855–872. doi: 10.1111/nan.12116
- Issue published online: 17 NOV 2014
- Article first published online: 17 NOV 2014
- Accepted manuscript online: 13 JAN 2014 02:01AM EST
- Manuscript Accepted: 8 JAN 2014
- Manuscript Received: 12 AUG 2013
- Medical Research Council PhD studentship
- Newby Fund (University of Edinburgh)
- British Neuropathological Society
- Scottish Funding Council
- British Heart Foundation Chair and Programme grant funding. Grant Numbers: CH98001, RG/07/005
- European Community's Seventh Framework Programme (FP7/2007-2013). Grant Number: HEALTH-F4-2010-241504
- blood brain barrier;
- lacunar stroke;
- neurovascular unit;
- small vessel disease;
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.
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.
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.
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.