Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China; Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Mol Cell Endocrinol. 2020 Apr 5;505:110731. doi: 10.1016/j.mce.2020.110731. Epub 2020 Jan 23.
In the mammalian ovary, the proteolysis of the extracellular matrix is dynamically regulated by plasminogen activator and plasminogen activator inhibitor (PAI), and it is a critical event that influences various physiological and pathological processes. Activin A is a member of the transforming growth factor-β superfamily and is expressed at a high level in human luteal cells that play an essential role in the regulation of the luteal function. At present, it is not known whether activin A can regulate the expression and production of PAI in human granulosa lutein (hGL) cells. The present study aimed to examine the effects of activin A on the expression and production of intraovarian PAI-1 and the underlying molecular mechanisms. Using primary and immortalized hGL cells as the cell model, we demonstrated that activin A upregulated the expression of PAI-1 and increased the production of PAI-1 in an autocrine/paracrine manner. Additionally, using a dual inhibition approach (molecular inhibitors and siRNA-mediated knockdown), we showed that this biological function is mediated by the ALK4-mediated SMAD3-SMAD4-dependent signaling pathway. Our findings suggest that activin A may be involved in the regulation of luteal function via the induction of PAI-1 expression and an increase in PAI-1 production.
在哺乳动物的卵巢中，细胞外基质的蛋白水解作用受到纤溶酶原激活物和纤溶酶原激活物抑制剂（PAI）的动态调节，这是一个影响各种生理和病理过程的关键事件。激活素 A 是转化生长因子-β超家族的一员，在人类黄体细胞中高表达，在黄体功能的调节中起着至关重要的作用。目前，尚不清楚激活素 A 是否可以调节人颗粒黄体细胞（hGL）中 PAI 的表达和产生。本研究旨在探讨激活素 A 对卵巢内 PAI-1 表达和产生的影响及其潜在的分子机制。本研究使用原代和永生化的 hGL 细胞作为细胞模型，证明激活素 A 以上调 PAI-1 的表达和自分泌/旁分泌方式增加 PAI-1 的产生。此外，通过双重抑制方法（分子抑制剂和 siRNA 介导的敲低），我们表明该生物学功能是由 ALK4 介导的 SMAD3-SMAD4 依赖性信号通路介导的。我们的研究结果表明，激活素 A 可能通过诱导 PAI-1 的表达和增加 PAI-1 的产生而参与黄体功能的调节。
