Down-Regulation of Circadian Clock Gene Period 2 in Uterine Endometrial Stromal Cells of Pregnant Rats During Decidualization

Abstract

Circadian rhythms are modulated in a variety of peripheral tissues, including in the uterus where endometrial stromal cells (UESCs) undergo proliferation and differentiation (decidualization) during gestation. Here the authors focused on circadian rhythms in UESCs during implantation and decidualization in rodents. As revealed by analyses of cultured UESCs from pregnant Per2 promoter–dLuc transgenic rats, Per2 oscillation of ∼24 h was observed in response to dexamethasone. Per2 oscillation was enhanced in UESCs during implantation, whereas they were attenuated during decidualization. In vivo studies showed that PER2 protein in the uteri displayed a peak at zeitberger time 4 (ZT 4) (day 4.50 of gestation) and a trough at ZT 12 (day 4.83), indicating its circadian rhythmicity. Conversely, no significant circadian rhythm of the PER2 protein was observed during decidualization. Fluorescent immunohistochemical studies also supported circadian rhythmicity of the PER2 protein in its intracellular distribution. In accordance with Per2 mRNA expression, a circadian rhythm of vascular endothelial growth factor (Vegf) gene expression, having several E-box or E-box–like sites at the upstream of the transcription start site, was observed during implantation, showing a peak at ZT 0 and a trough at ZT 12. In contrast, Vegf mRNA expression displayed no circadian rhythm during decidualization. Collectively, the present results prove that Per2 oscillation is down-regulated in UESCs during decidualization. It is strongly suggested that cellular differentiation in UESCs interferes with circadian clockwork. (Author correspondence: [email protected])

Keywords:

• Circadian rhythms
• Decidualization
• Implantation
• Per2
• Uterus
• Vegf

ACKNOWLEDGMENTS

We are grateful to Dr. Yoko Unoki Kato (Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University) for her help and advice with quantitative real-time PCR analyses. This work was funded by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Sciences (JSPS; 19658099, 22380152).

Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.