Institute for Maternal and Child Research (IDIMI), School of Medicine, University of Chile, Avenida Santa Rosa 1234, 8360160 Santiago-Centro, Santiago, Chile.
Computational Biology Lab (DLab), Fundación Ciencia & Vida. Avenida Zañartu 1482, 7780272 Ñuñoa, Santiago, Chile; Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Harrington 287, Valparaíso, Chile.
Steroids. 2019 Apr;144:21-29. doi: 10.1016/j.steroids.2019.02.004. Epub 2019 Feb 6.
An estradiol metabolite, 2-methoxyestradiol (2ME), has emerged as an important regulator of ovarian physiology. 2ME is recognized as a potent anti-angiogenic agent in clinical trials and laboratory studies. However, little is known about its molecular actions and its endogenous targets. 2ME is produced by human ovarian cells during the normal menstrual cycle, being higher during regression of the corpus luteum, and is postulated to be involved in the anti-angiogenic process that plays out during luteolysis. We utilized cell biology techniques to understand the molecular mechanism of 2ME anti-angiogenic effects on human granulosa luteal cells. The principal effect of 2ME was to alter Hypoxia Inducible Factor 1A (HIF1A) sub-cellular localization. Molecular modelling and multiple bioinformatics tools indicated that 2ME impairs Hypoxia Inducible Factor complex (HIF) nuclear translocation by binding to a buried pocket in the HIF1A Per Arnt Sim (PAS)-B domain. Binding of 2ME to HIF1A protein is predicted to perturb HIF1A-Hypoxia Inducible Factor B (HIFB) interaction, a key step in HIF nuclear translocation, preventing the transcriptional actions of HIF, including Vascular Endotelial Growth Factor (VEGF) gene activation. To our knowledge, 2ME is the first putative HIF endogenous ligand characterized with anti-angiogenic activity. This postulate has important implications for reproduction, because angiogenic processes are critical for ovarian follicular development, ovulation and corpus luteum regression. The present research could contribute to the development of novel pharmacological approaches for controlling HIF activity in human reproductive diseases.
一种雌二醇代谢物，2-甲氧基雌二醇（2ME），已成为卵巢生理学的重要调节因子。在临床试验和实验室研究中，2ME 被认为是一种有效的抗血管生成剂。然而，其分子作用及其内源性靶点知之甚少。在正常月经周期中，人卵巢细胞会产生 2ME，在黄体退化期间会升高，据推测其参与黄体溶解过程中的抗血管生成作用。我们利用细胞生物学技术来了解 2ME 对人颗粒黄体细胞抗血管生成作用的分子机制。2ME 的主要作用是改变低氧诱导因子 1A（HIF1A）的亚细胞定位。分子建模和多种生物信息学工具表明，2ME 通过与 HIF1A 蛋白 PAS-B 结构域中的一个埋藏口袋结合，损害缺氧诱导因子复合物（HIF）的核转位。2ME 与 HIF1A 蛋白的结合预计会扰乱 HIF1A-低氧诱导因子 B（HIFB）相互作用，这是 HIF 核转位的关键步骤，从而阻止 HIF 的转录作用，包括血管内皮生长因子（VEGF）基因的激活。据我们所知，2ME 是第一个具有抗血管生成活性的假定的 HIF 内源性配体。这一假设对生殖具有重要意义，因为血管生成过程对于卵巢卵泡发育、排卵和黄体退化至关重要。本研究可为控制人类生殖疾病中 HIF 活性的新型药理学方法的发展做出贡献。
