Estradiol-induced senescence of hypothalamic astrocytes contributes to aging-related reproductive function declines in female mice
Estradiol-induced senescence of hypothalamic astrocytes contributes to aging-related reproductive function declines in female mice
复制标题
雌二醇诱导的下丘脑星形胶质细胞衰老导致雌性小鼠与衰老相关的生殖功能下降
DOI：
10.18632/aging.103008
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发表时间：
2020-04-15
期刊：
影响因子：
5.2
通讯作者：
Zhang, Jing
中科院分区：
文献类型：
--
作者：
Dai, Xiaoman;Hong, Luyan;Zhang, Jing
下丘脑星形胶质细胞是激活促性腺激素释放激素(GnRH)神经元和促进GnRH/LH(黄体生成素)峰的重要贡献者。然而，星形胶质细胞在早期生殖衰退中的潜在作用和机制仍然不清楚。目前的研究报道，在完好的中年雌性小鼠中，下丘脑RP3V内的星形胶质细胞随着年龄的增长积累了衰老相关的标记。它采用了去卵巢的动物模型和接受雌激素干预的细胞模型来证实雌激素诱导的下丘脑星形胶质细胞衰老。研究发现，雌激素代谢产物可能是雌激素诱导星形胶质细胞衰老的重要因素。体外分子分析表明，卵巢雌激素激活了PKA，上调了细胞色素P450的表达，将雌二醇代谢为2-OHE2和4-OHE2。值得注意的是，在中年小鼠中，孕酮合成和促进GnRH释放的能力显著降低。此外，衰老的星形胶质细胞生长因子表达减少，促炎细胞因子的mRNA水平显著升高。结果证实，卵巢雌二醇诱导下丘脑星形胶质细胞衰老，衰老的星形胶质细胞影响孕酮合成和促性腺激素释放激素的分泌，这可能是导致女性生殖功能减退的原因之一。
Hypothalamic astrocytes are important contributors that activate gonadotropin-releasing hormone (GnRH) neurons and promote GnRH/LH (luteinizing hormone) surge. However, the potential roles and mechanisms of astrocytes during the early reproductive decline remain obscure. The current study reported that, in intact middle-aged female mice, astrocytes within the hypothalamic RP3V accumulated senescence-related markers with increasing age. It employed an ovariectomized animal model and a cell model receiving estrogen intervention to confirm the estrogen-induced senescence of hypothalamic astrocytes. It found that estrogen metabolites may be an important factor for the estrogen-induced astrocyte senescence. In vitro molecular analysis revealed that ovarian estradiol activated PKA and up-regulated CYPs expression, metabolizing estradiol into 2-OHE2 and 4-OHE2. Of note, in middle-aged mice, the progesterone synthesis and the ability to promote GnRH release were significantly reduced. Besides, the expression of growth factors decreased and the mRNA levels of proinflammatory cytokines significantly increased in the aging astrocytes. The findings confirm that ovarian estradiol induces the senescence of hypothalamic astrocytes and that the senescent astrocytes compromise the regulation of progesterone synthesis and GnRH secretion, which may contribute to the agingrelated declines in female reproductive function.