Center of Reproduction and Genetics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China.
Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Am J Physiol Endocrinol Metab. 2020 May 1;318(5):E710-E722. doi: 10.1152/ajpendo.00361.2019. Epub 2020 Jan 21.
There is increasing evidence showing the importance of vitamin D (Vit D) and its nuclear receptor, the Vit D receptor (VDR), in female reproductive health. Transforming growth factor-β1 (TGF-β1) and its functional receptors are expressed in human oocytes and granulosa cells that participate in follicular development and ovulation. Recently, Sma- and Mad-related protein 3 (SMAD3; a downstream effector of TGF-β1) has been proposed to mediate crosstalk between the Vit D and TGF-β1 signaling pathways, but this relationship has not been fully explored and has yet to be tested in human granulosa-lutein (hGL) cells. In this study, we showed that TGF-β1 significantly promoted the expression of VDR, and this stimulatory effect occurred through the activin receptor-like kinase 5 type I receptor-mediated SMAD3 and ERK1/2 signaling pathways in hGL cells. Additionally, we showed that Vit D increased the expression of cyclooxygenase 2 (COX-2) and the synthesis of prostaglandin E2 (PGE2) in a time- and dose-dependent manner. Furthermore, we demonstrated a synergistic effect of TGF-β1 and Vit D on the expression of COX-2 and synthesis of PGE2, and this effect could be attenuated by silencing the expression of VDR. Our findings indicate that TGF-β1 upregulates the expression of VDR, which promotes Vit D-induced COX-2 expression and subsequent PGE2 production by activating the SMAD3 and ERK1/2 signaling pathways in hGL cells.
越来越多的证据表明维生素 D（Vit D）及其核受体 Vit D 受体（VDR）在女性生殖健康中的重要性。转化生长因子-β1（TGF-β1）及其功能性受体在参与卵泡发育和排卵的人卵母细胞和颗粒细胞中表达。最近，Smad 和 Mad 相关蛋白 3（SMAD3；TGF-β1 的下游效应物）被提出介导 Vit D 和 TGF-β1 信号通路之间的串扰，但这种关系尚未得到充分探索，并且尚未在人颗粒细胞-黄体（hGL）细胞中进行测试。在这项研究中，我们表明 TGF-β1 显著促进了 VDR 的表达，这种刺激作用通过 hGL 细胞中激活素受体样激酶 5 型 I 受体介导的 SMAD3 和 ERK1/2 信号通路发生。此外，我们表明 Vit D 以时间和剂量依赖的方式增加了 COX-2 的表达和前列腺素 E2（PGE2）的合成。此外，我们证明了 TGF-β1 和 Vit D 对 COX-2 表达和 PGE2 合成的协同作用，并且这种作用可以通过沉默 VDR 的表达来减弱。我们的研究结果表明，TGF-β1 上调了 VDR 的表达，这通过激活 hGL 细胞中的 SMAD3 和 ERK1/2 信号通路促进了 Vit D 诱导的 COX-2 表达和随后的 PGE2 产生。
