Endocrine Abstracts

Glucocorticoids synchronise peripheral clocks with the master clock in the suprachiasmatic nucleus of the brain. In humans and mice, abnormal glucocorticoid rhythms induce blood pressure abnormalities accompanied by vascular dysfunction. The mechanisms of this remain unclear. We hypothesise that excessive activation of the glucocorticoid receptor (GR) disrupts circadian clock signalling, altering vascular function and inducing non-dipping blood pressure. We characterise the vascular molecular clock and define the rhythm of vascular reactivity in control mice and mice with smooth muscle specific deletion of the GR (SMGRKO). Mice were kept under 12:12 light: dark conditions. Plasma was sampled every 2 h across the light cycle and analysed for corticosterone by ELISA. Renal and mesenteric arteries were isolated at ZT0 and 12 (ZT0 lights on) to assess molecular clock transcripts by qPCR. Renal and mesenteric arteries from SMGRKO mice and controls were mounted on a wire myograph and subject to increasing doses of phenylephrine or sodium nitroprusside starting at ZT0 and ZT12 Data are mean±SD. Corticosterone had a circadian rhythm in control mice with peak at ZT 10. Clock genes Per1 and Bmal1 were expressed in the renal and mesenteric artery with a circadian rhythm peaking at ZT12 and ZT0 respectively. Vascular reactivity as assessed by wire myography showed in control mice the response to phenylephrine was elevated during the inactive period (ZT0, 86.2±9.21 % of the maximum constriction) compared to the active period (ZT 12, 72.3±7.52%). Relaxation in response to sodium nitroprusside was more pronounced during the active period (ZT12, 23.2±8.74% of pre-construction vs ZT0, 36.71±5.15%). The temporal differences in response to phenylephrine and SNP was absent in SMGRKO mice. These data suggest that glucocorticoids regulate the molecular components that control vascular function’s timing. Further investigations will identify glucocorticoid-related pathways that control vascular function and assess their impact on blood pressure rhythm.