Kristina Shkirkova, BSc
Clinical and epidemiological evidence suggests that cerebrovascular events are influenced by circadian rhythms. Due to changes in coagulative balance and vascular tone during a 24-hour period, strokes are observed to occur more often in the mornings followed by evenings, the second most prevalent time.1 Similarly, it was previously reported that variations in circadian blood pressure and microvascular perfusion influenced the incidence of subarachnoid hemorrhage (SAH).2
SAH neuronal damage and poor outcomes have been associated with changes to tissue perfusion. Since cellular mechanisms controlling circadian rhythms play an important role in cerebral blood flow autoregulation, circadian oscillation of microcirculation following SAH drive the cerebral perfusion rhythm. However, the evidence of circadian influence on neuronal injury after SAH remains elusive. The authors of the study by Lidington et al., recently published in Stroke, looked at cerebral resistance artery myogenic reactivity, a mechanism of cerebral blood flow autoregulation, which is strongly correlated with cerebral perfusion and neuronal injury after SAH.
To demonstrate circadian variations in cerebral resistance artery myogenic reactivity, the authors utilized a transgenic smooth muscle cell specific BMAL1 gene deletion mouse model. Pressure myography of the olfactory cerebral arteries in wild type mice confirmed presence of circadian rhythm, with highest at Zeitgeber Time (ZT) 23 and lowest at ZT11. However, in a transgenic smooth muscle cell-specific mouse model, BMAL1 gene deletion eliminated the observed circadian rhythm in arterial myogenic activity with a reverse pattern of peak at ZT11. Based on that data, the authors concluded that smooth muscle cell peripheral molecular clock drives the circadian rhythms of myogenic activity. Higher cerebral artery myogenic tone was correlated with reduced markers of perfusion and, as a result, with more severe SAH injury. At day 2 post SAH-induced injury at ZT23 compared to SAH-induced injury at ZT11, more neurons undergoing degeneration and apoptosis were observed. In transgenic mice, neurobehavioral deficits observed were higher for SAH injury at ZT11 than ZT23. These results indicate a close coupling of vascular circadian reactivity and SAH-induced injury level.
The authors also looked at the mRNA levels of cystic fibrosis transmembrane conductance regulator (CFTR). mRNA levels were reverse to myogenic activity, due to CFTR’s negative regulator role. At the protein level, CFTR is more highly expressed in ZT23 than ZT11, which is lost in the transgenic mice. This suggests that CFTR expression is intrinsic to smooth muscle cells rather than derived externally and it drives the circadian oscillations in arterial myogenic activity. Pretreatment of wild type mice with Lumacaftor drug, which increases the number of CFTR proteins that are trafficked to the cell surface, abolished the circadian pattern of arterial myogenic activity, and, as a result, no SAH-induced injury differences were observed throughout the 24-hour cycle.
The authors concluded that although multiple factors contribute to pathophysiology of SAH injury, microvascular constriction that is driven by intrinsic circadian clock is an important factor. CFRT-driven oscillations in microvascular constriction are an important mechanism and therapeutic target for SAH-induced brain injury.
1Manfredini R, Boari B, Smolensky MH, et al. Circadian variation in stroke onset: identical temporal pattern in ischemic and hemorrhagic events. Chronobiol Int. 2005;22(3):417-453. doi:10.1081/CBI-200062927
2 Kleinpeter G, Schatzer R, Böck F. Is blood pressure really a trigger for the circadian rhythm of subarachnoid hemorrhage?. Stroke. 1995;26(10):1805-1810. doi:10.1161/01.str.26.10.1805