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: qRT-PCR (Table S3) confirmed the microarray data for: MMP14 (down fivefold at 5 weeks, P < 0.01); GFAP (down twofold at 5 weeks, P = 0.01); and AVP (down fourfold at 5 weeks, P < 0.001) (Figure 5). qRT-PCR did not confirm the Alb, Gucy1a3, Mbp or Gpr98 findings. The Alb difference may be a ‘floor effect’ where low mRNA expression, detectable by the greater dynamic range of the mRNA microarray, was undetectable by qRT-PCR. Despite consistent >15-fold Gucy1a3 mRNA up-regulation in SHRSP at all ages in both brain sections, qRT-PCR showed no significant differences. Microarray and qRT-PCR probes examine different gene segments which are separated by >1000 nucleotides. Whole gene sequencing demonstrated a SNP in the 3′ untranslated region (UTR) of the Gucy1a3 gene at position 4379 (WKY cytosine, SHRSP thymine). Discrepancies between mRNA microarray, qRT-PCR and immunohistochemistry could be further explained either by a true functional difference caused by microRNA binding to the 3′UTR region , or by post-translational modification . Post-translational modification may be a result of over-exposure to a neurotransmitter or increased levels of reactive oxygen species  known to be present in the SHRSP .
Affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, Edinburgh; Department of Bioengineering, Imperial College London, London.