Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, China.
Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, China.
Am J Physiol Endocrinol Metab. 2021 Apr 1;320(4):E747-E759. doi: 10.1152/ajpendo.00466.2020. Epub 2021 Feb 8.
Prostaglandin G/H synthase 2 (PTGS2) is a rate-limiting enzyme in prostaglandin synthesis. The present study assessed the role of the uterine circadian clock on transcription in response to steroid hormones during early pregnancy. We demonstrated that the core clock genes (, , , and ), , and and their encoded proteins, have rhythmic expression in the mouse uterus from to () of pregnancy. Progesterone (P) treatment of cultured uterus endometrial stromal cells (UESCs) isolated from reporter gene knock-in mice on D4 induced a phase shift in oscillations. This P-induced phase shift of oscillations was significantly attenuated by the P antagonist RU486. Additionally, the amplitude of oscillations was increased by estradiol (E) treatment in the presence of P. Consistently, the mRNA levels of clock genes ( and ), , and were markedly increased by E treatment of UESCs in the presence of P. Treatment with E also promoted prostaglandin E (PGE) synthesis by UESCs. Depletion of in UESCs by small-interfering RNA (siRNA) decreased the transcript levels of clock genes ( and ), , and compared with nonsilencing siRNA treatment. knockdown also inhibited PGE synthesis. Moreover, the mRNA expression levels of clock genes ( and ), , and , and their respective proteins were significantly decreased in the uterus of mice. Thus, these data suggest that in mice promotes PGE synthesis by upregulating in response to increases in E on D4 of pregnancy. Rhythmic expression of Bmal1 and Ptgs2 was observed in the uterus isolated from of pregnant mice. E increased the expression of Bmal1 and Ptg2 in UESCs isolated from mice on D4. The expression of Ptgs2 was significantly decreased in Bmal1-siRNA treated UESCs. knockdown also inhibited PGE synthesis. Thus, these data suggest that Bmal1 in mice promotes PGE synthesis by upregulating Ptgs2 in response to increases in E on D4 of pregnancy.
前列腺素 G/H 合酶 2（PTGS2）是前列腺素合成的限速酶。本研究评估了子宫昼夜节律钟在妊娠早期对甾体激素反应中基因转录的作用。我们证明，核心时钟基因（、、、和）、和及其编码的蛋白质在妊娠第 4 天（）的小鼠子宫中具有节律性表达。孕激素（P）处理从妊娠第 4 天（）分离的报告基因敲入小鼠的培养子宫子宫内膜基质细胞（UESC）诱导时钟基因的相位偏移。这种 P 诱导的时钟基因振荡的相位偏移被 P 拮抗剂 RU486 显著减弱。此外，在 P 存在下，雌二醇（E）处理增加了时钟基因（和）、、和的振荡幅度。一致地，在 P 存在下，E 处理也增加了 UESC 的 mRNA 水平。用 E 处理还促进了 UESC 的前列腺素 E（PGE）合成。用小干扰 RNA（siRNA）敲低 UESC 中的可显著降低与非沉默 siRNA 处理相比，时钟基因（和）、、和的转录水平。 敲低也抑制了 PGE 合成。此外，在妊娠第 4 天（）的小鼠子宫中，时钟基因（和）、、和及其各自的蛋白质的 mRNA 表达水平显著降低。因此，这些数据表明，在怀孕第 4 天（），小鼠中的通过增加 E 来上调以促进 PGE 合成。在从怀孕第 4 天（）的小鼠中分离的子宫中观察到 Bmal1 和 Ptgs2 的节律性表达。E 增加了从怀孕第 4 天（）的小鼠中分离的 UESC 中 Bmal1 和 Ptg2 的表达。在 Bmal1-siRNA 处理的 UESC 中，Ptgs2 的表达显著降低。 敲低也抑制了 PGE 合成。因此，这些数据表明，在怀孕第 4 天（），小鼠中的通过增加 E 来上调以促进 PGE 合成。
