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

摘要 高血压在男性中比在年轻女性中更普遍，但随着女性逐渐 更年期时，这种关系是相反的。不幸的是，与男性相比，更年期女性更少 有可能得到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，在此之前和之后一直持续。 从45-54岁开始的绝经期。围绝经期伴随有 不规律的发情周期和不规律的雌激素水平波动；这也可能是 大脑可塑性的出现可能有助于高血压的发展。的反转 年轻和老年女性的高血压易感性可能在系统发育上是保守的：老年雌性小鼠， 但年轻的雌性小鼠没有，在缓慢加压后表现出交感神经张力和血压的增加 血管紧张素II(AngII)给药。为了更好地了解卵巢激素在女性体内的作用 高血压，我们利用了一种加速卵巢衰竭(AOF)的小鼠模型，该模型独特地 概述了人类更年期中的荷尔蒙波动。利用AOF小鼠，我们制作了一种新的 发现高血压的易感性始于“围产期”，这是一个以不规则为标志的阶段 并延长发情周期，类似于人类围绝经期。此外，围产期高血压是 与雌激素中N-甲基-D-天冬氨酸(NMDA)受体的独特可塑性有关 下丘脑室旁核内含有β受体(ER-β)的神经元 后AOF女性，或男性。这些发现将围产期定义为高血压和高血压的关键期 神经心血管调节系统的适应性出现了。在目前的提案中，我们将 探讨内质网β在高血压发病及下丘脑室旁核NMDA受体可塑性中的作用 佩里-奥夫。为此，我们将测试ERβ影响易感性的中心假设 围AOF小鼠部分PVN神经元群体的高血压和NMDA受体可塑性 在缓慢增压的安吉政府之后。两个目标将检验这一假设。目标一号将测试潜艇- 假设下丘脑室旁核中的ERβ与围绝经期女性 高血压和增强NMDA受体介导的CRF表达神经元的兴奋信号。 Aim 2将验证在围手术期循环应用ERβ激动剂可降低 含CRF的PVN高血压易感性及NMDA介导的兴奋性信号转导 神经元。这些研究将使用包括时空在内的多学科方法来实现。 ERβ基因缺失、电子显微镜免疫细胞化学、分子和生化分析 和神经生理学方法。

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.