Differential gene expression in multiple neurological, inflammatory and connective tissue pathways in a spontaneous model of human small vessel stroke.
Bottom Line: 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.Similar combined, individually modest, but multiple neurovascular unit defects, could explain susceptibility to spontaneous human SVD.
Affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, Edinburgh; Department of Bioengineering, Imperial College London, London.Show MeSH
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Mentions: Up-regulated inflammatory pathway genes indicate a chronically challenged immune system from early life also shown by others  which may trigger or accentuate the vascular and perivascular damage observed in older SHRSP compared with control strains. Several of the genes showing significant differential expression between SHRSP and WKY were downstream transcriptional targets of cAMP response element-binding protein (CREB) particularly the transcription factors (Figure 6). Genes regulated by CREB have been implicated in vascular remodelling in salt-induced hypertensive disease . We found no difference in mRNA expression of Creb1, but differential phosphorylation of Creb1, initiated by NO  could be the source of increased transcription factor expression, and if shown in future experiments, would provide further evidence of a central role for altered intracellular NO signalling.
Affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, Edinburgh; Department of Bioengineering, Imperial College London, London.