ISH NIA OS-06 PUTATIVE MECHANISMS FOR CEREBROVASCULAR REMODELLING IN THE SPONTANEOUSLY HYPERTENSIVE RAT (SHR) USING TRANSCRIPTOMICS.

Cerebrovascular remodeling in the SHR may be causative to the known brainstem hypoperfusion. Using RNA sequencing, we examined age-related processes that may govern remodeling of the cerebral arteries in the SHR.In SHR and their progenitor (normotensive) control (Wistar Kyoto, WKY), RNA-seq was performed at three ages: 5, 9, 13 weeks old. Cerebral arteries were flushed and peeled off the brain, stripped of meninges, snap frozen and RNA extracted. Ilumina platform, Ingenuity Pathway Analysis, histological examination of 5 weeks old basilar arteries by picrosirius red as well as second harmonics generation (SHG) microscopy were used.In the 5, 9 and 13 week old SHR, we identified 16, 10 and 17 pathways that were altered relative to WKY rats, respectively (p < 0.05), two were common at all age groups: fibrosis and antigen presentation. Pathways affected most at the pre-hypertensive age were those involved in the immune system (Graft-vs-Host, OX40, atherosclerosis, autoimmune thyroid disease signalling, dendritic cell maturation, and antigen presentation pathway). There was a marked increase of mRNA levels of several collagen subunits: col4α1, col6α2, col8α1, col9α2 col11α1, col16α1, col18α1 and col26α1. Based on these results, we hypothesised that altered fibrotic pathways would result in increased collagen content in basilar arteries contributing to their stiffness. Unexpectedly, total collagen type I and III stained with picrosirius red was diminished in 5 week old SHR vs WKY rat in: tunica externa (19% p < 0.01), tunica media (23%, p < 0.001). However, SHG showed increased fibrillogenesis in the tunica externa (F/B ratio 0.27 ± 0.13 vs 0.43 ± 0.3 for SHR and WKY, respectively, p = 0.014), whereas tunica media was unaffected.Remodeling of the cerebral arteries in the SHR may be induced, in part, by inflammation before the onset of hypertension. This triggers alterations in extracellular matrix and in vascular resistance thereby contributing to cerebral hypoperfusion.