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.

中文翻译：

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ALK4-SMAD3 / 4介导激活素A对人颗粒叶黄素细胞中PAI-1上调的影响。

在哺乳动物卵巢中，细胞外基质的蛋白水解受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超家族的成员，并在人类黄体细胞中高水平表达，而黄体细胞在黄体功能的调节中起重要作用。目前，尚不清楚激活素A是否能调节人颗粒叶黄素（hGL）细胞中PAI的表达和产生。本研究旨在检查激活素A对卵巢内PAI-1表达和产生的影响以及潜在的分子机制。使用原代和永生化的hGL细胞作为细胞模型，我们证明了激活素A以自分泌/旁分泌方式上调了PAI-1的表达并增加了PAI-1的产生。此外，使用双重抑制方法（分子抑制剂和siRNA介导的敲低），我们表明这种生物学功能是由ALK4介导的SMAD3-SMAD4依赖性信号传导途径介导的。我们的发现表明，激活素A可能通过诱导PAI-1表达和增加PAI-1的产量参与黄体功能的调节。