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

G蛋白偶联雌激素受体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影响

• 批准号: 10586855
• 负责人: MICHAEL J GLASS
• 金额: $ 75.94万
• 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 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586855
• 关键词: 4-vinylcyclohexene diepoxide; AMPA Receptors; Acceleration; Aging; Agonist; Anatomy; Angiotensin II; Animals; Area; Award; Biological; Blood Pressure; Brain; Cardiovascular Diseases; Cells; Characteristics; Coupled; Data; Diagnostic; Dissociation; ESR1 gene; Estrogen Receptor beta; Estrogens; Event; Female; GPER gene; Gender; Gene Silencing; Gene Targeting; Gene Transfer; Genes; Genetic Transcription; Glutamate Receptor; Gonadal Steroid Hormones; Grant; Hormonal; Hormonal Change; Human; Hypertension; Hypothalamic structure; Immunoelectron Microscopy; In Situ Hybridization; Incidence; Literature; Mediating; Menopause; Modeling; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Neurosecretory Systems; Ovariectomy; Perimenopause; Play; Postmenopause; Pre-Clinical Model; Predisposition; Process; Production; Receptor Signaling; Resolution; Risk; Rodent Model; Role; Sex Differences; Signal Pathway; Signal Transduction; Synaptic plasticity; Testing; Therapeutic; Tissue-Specific Gene Expression; Transcriptional Regulation; Woman; blood pressure control; blood pressure elevation; blood pressure regulation; cardiovascular disorder risk; cardiovascular risk factor; cell type; emerging adult; glutamatergic signaling; grasp; in vivo; male; men; middle age; modifiable risk; mouse model; multidisciplinary; neurogenic hypertension; neuromechanism; neurophysiology; novel; ovarian failure; paraventricular nucleus; patch clamp; pre-clinical; prevent; single-cell RNA sequencing; transcriptomics

Although the increase in hypertension and cardiovascular disease-risk at menopause is well-recognized, the mechanisms of menopausal hypertension are still inadequately understood. Irregular cycles and declining levels of estrogen have been suspected to play a critical role in the emergence of hypertension at the onset of menopause. However, a clear understanding of estrogen’s role in menopausal hypertension has been limited by the confounding effects of variables such as aging in the human literature and the use of models primarily reliant on the use of ovariectomized animals that do not replicate natural menopause in the preclinical literature. Significantly, a mouse model of accelerated ovarian failure (AOF) induced by 4-vinylcyclohexene diepoxide (VCD) can recapitulate early (i.e., peri-AOF) and late (i.e., post-AOF) stages of human peri- and postmenopause, respectively. The AOF model has proven effective in isolating the role of sex hormones in blood pressure, particularly with respect to models of neurogenic hypertension involving the hypothalamic paraventricular nucleus (PVN), a brain area critical for coordinating sympathetic and neurohumoral processes important for the regulation of blood pressure. In the last grant award, we found that peri-AOF hypertension induced by slow- pressor angiotensin II (AngII) was associated with a signaling pathway involving estrogen receptor beta (ERb) and the NMDA-type glutamate receptor in PVN neurons. It is important to recognize that after perimenopause women transition to postmenopause, however, it is unclear if the mechanisms of hypertension during postmenopause are mediated by similar mechanisms. In pilot data, we show that hypertension at post-AOF is associated with altered signaling involving GluA1-expressing AMPA, but not NMDA receptors. We further show that administration of an agonist of the G-protein coupled estrogen receptor 1 (GPER), but not ERb, inhibits AngII hypertension in post-AOF mice. In this proposal, we will test the central hypothesis that post-AOF mice are predisposed to hypertension that is dependent on GluA1 plasticity in the PVN and alleviated by GPER signaling. Two aims will test this hypothesis. Aim 1 tests the sub-hypothesis that alterations in PVN GluA1 signaling contribute to hypertension in post-AOF mice. Aim 2 tests the sub-hypothesis that post-AOF hypertension is associated with GPER signaling in the PVN. These studies will be performed using a combination of approaches including high-resolution anatomical, neurophysiological, in vivo gene targeting, and single-cell RNA sequencing approaches.

虽然绝经期高血压和心血管疾病风险的增加是众所周知的， 绝经期高血压的机制仍不完全清楚。周期不规则和水平下降 雌激素的水平被怀疑在高血压发病时起关键作用。 绝经然而，对雌激素在绝经期高血压中的作用的清楚理解是有限的 受人类文献中的年龄等变量的混杂效应和主要使用模型的影响， 依赖于使用卵巢切除动物，这些动物不能复制临床前文献中的自然绝经期。 值得注意的是，由4-乙烯基环己烯二环氧化物诱导的加速卵巢衰竭（AOF）小鼠模型 (VCD)可以早期重演（即，围AOF期）和晚期（即，AOF后）人绝经期和绝经后阶段， 分别AOF模型已被证明在分离性激素在血压中的作用方面是有效的， 特别是对于涉及下丘脑室旁核的神经源性高血压模型 核（PVN），一个对协调交感神经和神经体液过程至关重要的脑区， 调节血压。在上一次的研究中，我们发现AOF周围的高血压是由缓慢的- 升压血管紧张素II（AngII）与涉及雌激素受体β（ERb）的信号通路相关 和室旁核神经元中的NMDA型谷氨酸受体。重要的是要认识到， 然而，妇女过渡到绝经后，尚不清楚高血压的机制， 绝经后妇女也是由类似的机制介导的。在试点数据中，我们表明AOF后的高血压是 与涉及表达GluA 1的AMPA而非NMDA受体的信号传导改变相关。进一步的研究表明 给予G蛋白偶联雌激素受体1（GPER）激动剂，而不是ERb， AOF后小鼠的AngII高血压。在这个提议中，我们将测试中心假设，即后AOF小鼠 易患高血压，高血压依赖于室旁核中的GluA 1可塑性，并由GPER缓解 发信号。两个目标将检验这一假设。目的1检验PVN GluA 1的改变 信号传导导致AOF后小鼠的高血压。目的2检验AOF后 高血压与PVN中的GPER信号传导相关。这些研究将使用 包括高分辨率解剖学、神经生理学、体内基因靶向和 单细胞RNA测序方法。