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Estradiol-Induced Senescence of Hypothalamic Astrocytes Contributes to Aging-Related Reproductive Function Declines in Female Mice
66 Pages Posted: 2 Mar 2020
More...Abstract
Background: Hypothalamic astrocytes are the important contributors that activate gonadotropin-releasing hormone (GnRH) neurons and promote GnRH/LH (luteinizing hormone) surge. However, the underlying roles and mechanisms of astrocytes during the early age reproductive decline remain unclear.
Methods: Immunofluorescence and immunohistochemical staining were applied to analyze the expression of p16, γ-H2AX, SA-β-Gal and peroxidase. Animal ovariectomized models and cell models receiving repeated estradiol intervention were adopted to investigate estradiol-induced astrocyte senescence. High-performance liquid chromatography (HPLC) was employed to detect the estradiol metabolites and progesterone. qPCR and western blot were performed to analyze the PKA-CYPs pathway, growth factors and proinflammatory cytokines.
Findings: Intact middle-aged female mice, astrocytes within the hypothalamic RP3V accumulate senescence-related markers with increasing age. Molecular analysis revealed that ovarian estradiol activated PKA and up-regulated CYPs (cytochrome p450) expression, metabolizing estradiol into 2-OHE2 and 4-OHE2 and mediating the senescence of astrocytes in RP3V. Of note, the progesterone synthesis and the ability to promote GnRH release were significantly reduced in middle-aged mice. Besides, the expression of growth factors decreased and the mRNA levels of proinflammatory cytokines significantly increased in the aging astrocytes.
Interpretation: The findings confirm that ovarian estradiol induces the senescence of hypothalamic astrocytes. The senescent astrocytes compromises the function for regulating progesterone synthesis and GnRH secretion, may be contributes to aging-related declines in female reproductive function.
Funding Statement: The study was supported by National Natural Science Foundation of China to Jing Zhang (No.81671400) and Fujian Province Health and Family Planning Youth Research Project to Xiaoman Dai(No.2018-1-45).
Declaration of Interests: All authors have no potential conflicts of interests to declare, financial or otherwise
Ethics Approval Statement: All protocols and procedures used in these studies involving animals were approved by the Institutional Animal Care and Use Committee of Fujian Medical University and in compliance with NIH’s Guidelines for the Care and Use of Laboratory Animals (NIH Publication No. 85-23 Rev. 1985). This article does not contain any studies with human participants performed by any of the authors.
Keywords: Estradiol; Aging; Hypothalamic astrocyte; Reproduction; GnRH
Suggested Citation: Suggested Citation