Contribution of estrogen receptor beta to changes in hypothalamic plasticity and hypertension susceptibility in mice with accelerated ovarian failure

雌激素受体β对卵巢加速衰竭小鼠下丘脑可塑性和高血压易感性变化的贡献

• 批准号: 9420655
• 负责人: MICHAEL J GLASS
• 金额: $ 42.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9420655
• 关键词: Age; Age-Years; Agonist; Angiotensin II; Angiotensins; Antihypertensive Agents; Area; Argipressin; Binding; Biochemical; Biological; Biological Assay; Blood; Blood Pressure; Brain; Cardiovascular system; Cell membrane; Corticotropin-Releasing Hormone; Dendrites; Development; Diagnostic; Disease; Electrons; Electrophysiology (science); Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Estrous Cycle; Evaluation; Female; Fostering; Genes; Glutamates; Hormones; Human; Hypertension; Hypothalamic structure; Immunoelectron Microscopy; In Situ; Incidence; Intervention; Investigation; Label; LoxP-flanked allele; Mediating; Menopause; Methods; Microscopic; Modeling; Molecular; Mus; N-Methylaspartate; Neuronal Plasticity; Neurons; Neurosecretory Systems; Nitric Oxide; Obesity; Ovarian hormone; Pathway interactions; Perimenopause; Periodicity; Phase; Phase Transition; Phylogenetic Analysis; Population; Postmenopause; Predisposition; Premenopause; Process; Production; Quantitative Reverse Transcriptase PCR; Reactive Oxygen Species; Regulation; Reporter; Rodent; Role; Signal Transduction; Signaling Molecule; Slice; Stress; System; Testing; Therapeutic; Therapeutic Intervention; Time; Western Blotting; Woman; aged; aspartate receptor; blood pressure regulation; critical period; density; human model; hypertension control; immunocytochemistry; interdisciplinary approach; male; men; mouse model; neurodevelopment; neurophysiology; novel; older women; ovarian failure; paraventricular nucleus; receptor-mediated signaling; relating to nervous system; salt intake; spatiotemporal; trafficking; young woman; Age; Age-Years; Agonist; Angiotensin II; Angiotensins; Antihypertensive Agents; Area; Argipressin; Binding; Biochemical; Biological; Biological Assay; Blood; Blood Pressure; Brain; Cardiovascular system; Cell membrane; Corticotropin-Releasing Hormone; Dendrites; Development; Diagnostic; Disease; Electrons; Electrophysiology (science); Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Estrous Cycle; Evaluation; Female; Fostering; Genes; Glutamates; Hormones; Human; Hypertension; Hypothalamic structure; Immunoelectron Microscopy; In Situ; Incidence; Intervention; Investigation; Label; LoxP-flanked allele; Mediating; Menopause; Methods; Microscopic; Modeling; Molecular; Mus; N-Methylaspartate; Neuronal Plasticity; Neurons; Neurosecretory Systems; Nitric Oxide; Obesity; Ovarian hormone; Pathway interactions; Perimenopause; Periodicity; Phase; Phase Transition; Phylogenetic Analysis; Population; Postmenopause; Predisposition; Premenopause; Process; Production; Quantitative Reverse Transcriptase PCR; Reactive Oxygen Species; Regulation; Reporter; Rodent; Role; Signal Transduction; Signaling Molecule; Slice; Stress; System; Testing; Therapeutic; Therapeutic Intervention; Time; Western Blotting; Woman; aged; aspartate receptor; blood pressure regulation; critical period; density; human model; hypertension control; immunocytochemistry; interdisciplinary approach; male; men; mouse model; neurodevelopment; neurophysiology; novel; older women; ovarian failure; paraventricular nucleus; receptor-mediated signaling; relating to nervous system; salt intake; spatiotemporal; trafficking; young woman

ABSTRACT Hypertension is more prevalent in men than in young women, but as women progress towards menopause this relationship is reversed. Unfortunately, compared to men, menopausal women are less likely to receive optimal diagnostic evaluation and therapeutic intervention. In women, the increased incidence of hypertension begins at “perimenopause”, a transitional phase preceding and extending through menopause beginning at ~45-54 years of age. The perimenopausal period is accompanied by irregular estrous cycles and erratically fluctuating estrogen levels; it may also be a critical period for the emergence of brain plasticity that may contribute to the development of hypertension. The reversal of hypertension liability in young and older women may be phylogenetically conserved: aged female mice, but not young female mice, show increased sympathetic tone and blood pressure following slow-pressor angiotensin II (AngII) administration. To better understand the role of ovarian hormones in female hypertension, we have utilized a mouse model of accelerated ovarian failure (AOF) that uniquely recapitulates hormone fluctuations seen in human menopause. Using AOF mice, we made the novel finding that the susceptibility to hypertension begins at “peri-AOF”, which is a stage marked by irregular and extended estrous cycles similar to human perimenopause. In addition, peri-AOF hypertension was associated with a unique profile of N-methyl-D-aspartic acid (NMDA) receptor plasticity in estrogen receptor β (ERβ) containing neurons in the hypothalamic paraventricular nucleus (PVN) not seen in pre- or post-AOF females, or in males. These findings define peri-AOF as a critical period when hypertension and adaptations in neuro-cardiovascular regulatory systems emerge. In the current proposal, we will investigate the role of ERβ in the emergence of hypertension and PVN NMDA receptor plasticity during peri-AOF. For this, we will test the central hypothesis that ERβ influences the susceptibility to hypertension and NMDA receptor plasticity in select populations of PVN neurons in peri-AOF mice following slow-pressor AngII administration. Two aims will test this hypothesis. Aim 1 will test the sub- hypothesis that ERβ in the PVN is critically involved in the susceptibility of peri-AOF females to hypertension and potentiated NMDA receptor-mediated excitatory signaling in CRF-expressing neurons. Aim 2 will test the sub-hypothesis that cyclic administration of ERβ agonists during peri-AOF reduces both hypertension susceptibility and NMDA-mediated excitatory signaling selectively in CRF-containing PVN neurons. These studies will be achieved using a multidisciplinary approach including spatio-temporal deletion of the ERβ gene, electron microscopic immunocytochemistry, molecular and biochemical assays and neurophysiological methods.

抽象的 与年轻女性相比，男性高血压更为普遍，但随着女性的发展 更年期这种关系颠倒了。不幸的是，与男人相比，更年期的女人少 可能会接受最佳的诊断评估和治疗干预。在女性中，增加 高血压发病率始于“围绝经期”，这是一个先于和延伸的过渡阶段 通过更年期开始，从〜45-54岁开始。围绝经期是通过 不规则的发情周期和不规则波动的雌激素水平；对于 大脑可塑性的出现可能有助于高血压的发展。逆转 年轻女性和老年妇女的高血压责任可能是组织的：老年雌性小鼠， 但不是年轻的雌性小鼠，表现出慢速慢速的同情性语气和血压增加 血管紧张素II（Angii）给药。更好地了解卵巢激素在女性中的作用 高血压，我们使用了一个唯一的卵巢衰竭（AOF）的小鼠模型 概括了在人类更年期中看到的马内波动。使用AOF鼠标，我们制作了小说 发现高血压的敏感性始于“ peri-aof”，这是一个不规则的阶段 并扩展了与人类围栏类似的发情循环。此外，高血压周期为 与雌激素中N-甲基-D-天冬氨酸（NMDA）受体可塑性的独特特征有关 在前或未见 女性或男性。这些发现将高压和高血压的关键时期定义为 出现了神经血管血管调节系统的适应性。在当前的建议中，我们将 研究ERβ在高血压和PVN NMDA受体可塑性中的出现中的作用 毛骨子。为此，我们将测试中心假设，即ERβ会影响对 小鼠周围PVN神经元的某些群体中的高血压和NMDA受体可塑性 在缓慢的ANGII给药之后。两个目标将检验这一假设。 AIM 1将测试子 假设PVN中的ERβ与女性对骨的敏感性有关 在表达CRF的神经元中的高血压和潜在的NMDA受体介导的兴奋性信号传导。 AIM 2将测试以下亚物种，即在骨周期期间循环施用ERβ激动剂可降低两者 高血压易感性和NMDA介导的兴奋性信号在含CRF的PVN中有选择性 神经元。这些研究将使用多学科的方法来实现，包括时空 ERβ基因，电子显微镜免疫细胞化学，分子和生化测定的缺失 和神经生理方法。