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

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.

摘要 高血压在男性中比在年轻女性中更普遍，但随着女性向高血压发展， 更年期这种关系是颠倒的。不幸的是，与男性相比，更年期女性的情况较少 可能接受最佳的诊断评估和治疗干预。在女性中， 高血压的发病始于“围绝经期”，这是一个过渡期， 从45-54岁开始绝经。围绝经期伴随着 不规则的动情周期和不稳定的雌激素水平;这也可能是一个关键时期 大脑可塑性的出现可能有助于高血压的发展。拨回 年轻和老年妇女的高血压倾向可能是遗传上保守的：老年雌性小鼠， 而不是年轻的雌性小鼠，显示出增加交感神经张力和血压后， 血管紧张素II（AngII）给药。为了更好地了解卵巢激素在女性中的作用， 高血压时，我们利用了一种加速卵巢衰竭（AOF）的小鼠模型， 再现了人类更年期的激素波动。使用AOF小鼠，我们制作了 发现高血压的易感性开始于“围AOF”，这是一个以不规则 和延长的发情周期类似于人类的围绝经期。此外，AOF周围高血压是 与雌激素中N-甲基-D-天冬氨酸（NMDA）受体可塑性的独特特征相关 在下丘脑室旁核（PVN）中，未观察到含有ERβ受体的神经元， AOF后的女性或男性。这些发现将AOF围手术期定义为高血压和 神经-心血管调节系统的适应出现。在目前的提案中，我们将 探讨ERβ在高血压发生中的作用及PVN NMDA受体的可塑性 围AOF为此，我们将检验中心假设，即ERβ影响对 高血压与围AOF小鼠室旁核神经元NMDA受体可塑性 慢升压血管紧张素II给药后。两个目标将检验这一假设。目标1将测试潜艇 PVN中的ERβ与AOF周围女性对以下疾病的易感性密切相关的假设： 高血压和增强NMDA受体介导的CRF表达神经元的兴奋性信号传导。 目的2将检验在AOF围手术期周期性给予ERβ激动剂可降低 高血压易感性和NMDA介导CRF室旁核选择性兴奋信号 神经元这些研究将采用多学科方法，包括时空 ERβ基因缺失、电镜免疫细胞化学、分子生物学检测 和神经生理学方法。