Differential Regulation of BMAL1, CLOCK, and Endothelial Signaling in the Aortic Arch and Ligated Common Carotid Artery

Abstract

The circadian clock is rhythmically expressed in blood vessels, but the interaction between the circadian clock and disturbed blood flow remains unclear. We examined the relationships between BMAL1 and CLOCK and 2 regulators of endothelial function, AKT1 and endothelial nitric oxide synthase (eNOS), in vascular regions of altered blood flow. We found that the aortic arch from WT mice exhibited reduced sensitivity to acetylcholine (Ach)-mediated relaxation relative to the thoracic aorta. In Clock-mutant (mut) mice the aorta exhibited a reduced sensitivity to Ach. In WT mice, the phosphorylated forms of eNOS and AKT were decreased in the aortic arch, while BMAL1 and CLOCK expression followed a similar pattern of reduction in the arch. In conditions of surgically induced flow reduction, phosphorylated-eNOS (serine 1177) increased, as did p-AKT in the ipsilateral left common carotid artery (LC) of WT mice. Similarly, BMAL1 and CLOCK exhibited increased expression after 5 days in the remodeled LC. eNOS expression was increased at 8 p.m. versus 8 a.m. in WT mice, and this pattern was abolished in mut and Bmal1-KO mice. These data suggest that the circadian clock may be a biomechanical and temporal sensor that acts to coordinate timing, flow dynamics, and endothelial function.