2.2. The cystic fibrosis transmembrane conductance regulator (CFTR) as a potential link between the molecular clock and myogenic responsiveness in cerebral arteries

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Oral 2 - 2.2

1Chloe Ng, 1Jeffrey T. Kroetsch, 1Darcy Lidington, 1Steffen-Sebastian Bolz

1 Department of Physiology, University of Toronto, Ontario, Canada

Cerebral autoregulation maintains constant cerebral perfusion despite varying input in the form of oscillating mean arterial pressure (MAP). Cerebral autoregulation is achieved through the myogenic response: the intrinsic ability of cerebral resistance arteries to adapt their tone to prevalent pressures. Circadian MAP oscillations challenge cerebral autoregulation rhythmically; we therefore hypothesize that the molecular clock within cerebral arteries enables them to adapt their cerebrovascular myogenic reactivity in anticipation of these varying systemic input pressures.

Myogenic and phenylephrine-stimulated vasoconstriction was determined in mouse olfactory arteries using pressure myography at Zeitgeber times (ZT) 3, 7, 11, 15, 19, 23 (n=6-8 for each ZT). Expression of microvascular clock gene mRNA (Bmal1, Clock, and Per2, n=3) at the same ZTs was analyzed by qPCR. A working peripheral molecular clock in these arteries was confirmed since Bmal1, Clock, and Per2 showed typical oscillations. We examined the mRNA expression of 3 key myogenic signalling targets (sphingosine kinase 1, S1P receptor 2 and cystic fibrosis transmembrane regulator, CFTR) and found that only CFTR mRNA oscillates. CFTR protein expression was similar to mRNA expression, being higher at ZT11 than ZT23 (n=6). Myogenic vasoconstriction displayed circadian rhythmicity, with a peak and trough that matched CFTR’s function as a negative regulator of myogenic reactivity. In contrast to myogenic vasoconstriction, phenylephrine-stimulated vasoconstriction did not exhibit circadian rhythmicity.

In summary, the cerebral microvasculature exhibits circadian rhythmicity in myogenic responsiveness, which allows for adjustment to circadian oscillations in systemic input pressures (i.e., MAP). At the molecular level, our data suggest that CFTR, a key myogenic signalling element, plays a role in the link between the molecular clock and this functional phenotype.