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首页> 外文期刊>Endocrinology >Signaling by hypoxia-inducible factors is critical for ovulation in mice.
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Signaling by hypoxia-inducible factors is critical for ovulation in mice.

机译：缺氧诱导因子的信号传导对小鼠排卵至关重要。

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The steroid hormone progesterone, acting via its nuclear receptor, is a major regulator of the process of ovulation. Female mice lacking progesterone receptor (PGR) exhibit an anovulatory phenotype due to failure in follicular rupture. To identify the PGR-regulated pathways that control ovulation, we analyzed global changes in gene expression in the ovaries of wild-type and Pgr-null mice subjected to gonadotropin-induced superovulation. Our analysis uncovered several genes whose expression was reduced in the Pgr-null ovaries compared with the wild-type ovaries immediately preceding ovulation. Interestingly, these genes included three hypoxia-inducible factors (HIFs): HIF-1 alpha, HIF-2 alpha, and HIF-1 beta. These transcription factors form alphabeta-heterodimers, which regulate the transcription of specific cellular genes, thereby mediating adaptive response of the tissue to low-oxygen levels. We observed that the expression of mRNAs and proteins corresponding to HIF-1 alpha, HIF-2 alpha, and HIF-1 beta was induced in a PGR-dependent manner, specifically in the granulosa cells of the preovulatory follicles. Inhibition of the HIF transcriptional activity by echinomycin, a small-molecule inhibitor that suppresses the binding of HIF alphabeta-heterodimers to target genes, blocked ovulation by preventing the rupture of the preovulatory follicles. Echinomycin specifically inhibited the expression of genes that are known regulators of ovulation, such as a disintegrin and metalloproteinase with thrombospondin-like motifs-1 and endothelin-2. Furthermore, echinomycin reduced the expression of vascular endothelial growth factor A, a key factor controlling vascularization/angiogenesis during ovulation. Collectively, these findings unveiled a novel ovarian role for the HIF transcription factors during the ovulatory period in mice.
机译：类固醇激素孕酮通过其核受体起作用，是排卵过程的主要调节剂。缺乏孕激素受体（PGR）的雌性小鼠由于卵泡破裂失败而表现出无排卵表型。为了确定PGR调控的控制排卵的途径，我们分析了促性腺激素诱导的超排卵的野生型和Pgr无小鼠的卵巢中基因表达的总体变化。我们的分析发现了几个基因，与排卵前的野生型卵巢相比，其在Pgr无卵巢中的表达降低了。有趣的是，这些基因包括三个缺氧诱导因子（HIF）：HIF-1 alpha，HIF-2 alpha和HIF-1 beta。这些转录因子形成字母异二聚体，其调节特定细胞基因的转录，从而介导组织对低氧水平的适应性反应。我们观察到对应于HIF-1 alpha，HIF-2 alpha和HIF-1 beta的mRNA和蛋白的表达以PGR依赖性方式被诱导，特别是在排卵前卵泡的颗粒细胞中。棘霉素（一种抑制HIF字母异二聚体与靶基因的结合的小分子抑制剂）对HIF转录活性的抑制，通过防止排卵前卵泡破裂而阻止了排卵。棘霉素特别抑制已知的排卵调节基因的表达，例如具有血小板反应蛋白样基序1和内皮素2的双整合素和金属蛋白酶。此外，棘轮霉素降低了血管内皮生长因子A的表达，血管内皮生长因子A是控制排卵过程中血管化/血管生成的关键因素。这些发现共同揭示了小鼠排卵期HIF转录因子在卵巢中的新作用。

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