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

Emma L. Bailey, Martin W. Mcbride, Wendy Crawford, John D. Mcclure, Delyth Graham, Anna F. Dominiczak, Catherine Sudlow, Colin Smith, Joanna M. Wardlaw

Research output: Contribution to journalArticlepeer-review

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-PCR and 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.
Original languageEnglish
Pages (from-to)855-872
JournalNeuropathology and Applied Neurobiology
Volume40
Issue number7
DOIs
Publication statusPublished - 2014

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