BMAL1 Disrupted Intrinsic Diurnal Oscillation in Rat Cerebrovascular Contractility of Simulated Microgravity Rats by Altering Circadian Regulation of miR-103/CaV1.2 Signal Pathway.

Li Chen,Hong-Zhe Ma,Man-Jiang Xie,Bin Zhang,Yun-Gang Bai,Jin Ma,Jiu-Hua Cheng,Ji-Bo Song,Lu Yang,Yi-Ling Ge

doi:10.3390/ijms20163947

Li Chen, Hong-Zhe Ma + Show 8 more

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https://doi.org/10.3390/ijms20163947

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Abstract

The functional and structural adaptations in cerebral arteries could be one of the fundamental causes in the occurrence of orthostatic intolerance after space flight. In addition, emerging studies have found that many cardiovascular functions exhibit circadian rhythm. Several lines of evidence suggest that space flight might increase an astronaut’s cardiovascular risks by disrupting circadian rhythm. However, it remains unknown whether microgravity disrupts the diurnal variation in vascular contractility and whether microgravity impacts on circadian clock system. Sprague-Dawley rats were subjected to 28-day hindlimb-unweighting to simulate the effects of microgravity on vasculature. Cerebrovascular contractility was estimated by investigating vasoconstrictor responsiveness and myogenic tone. The circadian regulation of CaV1.2 channel was determined by recording whole-cell currents, evaluating protein and mRNA expressions. Then the candidate miRNA in relation with Ca2+ signal was screened. Lastly, the underlying pathway involved in circadian regulation of cerebrovascular contractility was determined. The major findings of this study are: (1) The clock gene BMAL1 could induce the expression of miR-103, and in turn modulate the circadian regulation of CaV1.2 channel in rat cerebral arteries at post-transcriptional level; and (2) simulated microgravity disrupted intrinsic diurnal oscillation in rat cerebrovascular contractility by altering circadian regulation of BMAL1/miR-103/CaV1.2 signal pathway.

Highlights

Postflight orthostatic intolerance has been considered as one of the major adverse effects after spaceflight, in which multiple mechanisms have been reported to be implicated, such as hypovolemia, altered neurohumoral regulation and aerobic capacity, alterations in baroreflex sensitivity, and cardiovascular dysfunction [1,2]
By investigating vasoconstrictor responsiveness and myogenic tone, we found that there was an existence of diurnal variation in rat cerebrovascular contractility with the higher amplitude in the subjective light period(ZT4) and the lower in the subjective dark period(ZT16), which is similar to the previous reports of a circadian rhythm in vascular contractility with a peak at the beginning light phase in nocturnal animals [7,8,10]
We found that simulated microgravity markedly increased the cerebrovascular contractility at both zeitgeber time 4 (ZT4) and ZT16, whereas significantly suppressed the intrinsic diurnal variation of rat cerebral vascular contractility

Summary

Introduction

Postflight orthostatic intolerance has been considered as one of the major adverse effects after spaceflight, in which multiple mechanisms have been reported to be implicated, such as hypovolemia, altered neurohumoral regulation and aerobic capacity, alterations in baroreflex sensitivity, and cardiovascular dysfunction [1,2]. Ground-based animal studies with tail-suspended (SUS) hindlimb-unweighting rat models have clearly demonstrated that simulated microgravity induces the hypertrophic remodeling in cerebral arteries including increased media thickness, augmented myogenic tone, enhanced arterial reactivity, and impaired endothelial function [3] All these findings suggest that functional and structural adaptations in cerebral arteries are fundamental causes in the occurrence of postflight orthostatic intolerance, but the underlying mechanisms remain to be fully clarified [1,3]. Upon accumulation in the cytoplasm, the protein products of Per and Cry translocate to the nucleus and inhibit CLOCK/BMAL1-mediated transcription as negative elements, which leads to repression of their own transcription This core loop is interconnected with additional positive and negative regulatory loops, including nuclear receptors such as REV-ERBα (NR1D1, nuclear receptor subfamily 1, group D, member 1), RORα (RAR-related orphan receptor alpha), and PPARs (Peroxisome proliferator-activated receptors). These clock genes control numerous target genes (clock-controlled genes, CCGs) and work as transcription factors to produce the diurnal rhythmic expression in approximately 10% of genomic genes, which in turn provide the diurnal variation for cardiovascular function [6]

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