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.

尽管更年期高血压和心血管疾病风险的增加是众所周知的，但 绝经期高血压的发病机制仍不十分清楚。不规则的周期和下降的水平 雌激素被怀疑在高血压的发病中起着关键作用。 更年期。然而，对雌激素在更年期高血压中的作用的清楚了解一直是有限的 通过人类文献中的年龄等变量的混杂影响和主要模型的使用 依赖于临床前文献中不复制自然更年期的卵巢切除动物的使用。 值得注意的是，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)可以概括人类围绝经期和绝经期的早期(即围绝经期)和晚期(即绝经期后)， 分别进行了分析。AOF模型已被证明在分离性激素对血压的作用方面是有效的， 尤其是涉及下丘脑室旁核的神经源性高血压模型 核团(PVN)，大脑的一个区域，对协调交感和神经体液过程至关重要，对 调节血压。在上一次的拨款中，我们发现慢性高血压引起的围产期高血压。 升压血管紧张素II(AngII)与雌激素受体β(Erb)相关的信号通路 下丘脑室旁核神经元的NMDA型谷氨酸受体。重要的是要认识到在围绝经期之后 然而，妇女过渡到绝经后，高血压的机制是否在绝经期间尚不清楚 绝经后也有类似的调节机制。在试点数据中，我们表明AOF后的高血压是 与涉及表达GluA1的AMPA而不是NMDA受体的信号改变有关。我们进一步展示了 给予G蛋白偶联雌激素受体1(GPER)的激动剂，而不是ERb，抑制 AOF后小鼠的血管紧张性高血压。在这项提案中，我们将检验AOF后小鼠的中心假设 容易患高血压，这种高血压依赖于PVN中GluA1的可塑性，并可通过GPER缓解 发信号。两个目标将检验这一假设。Aim 1检验PVN GluA1改变的亚假说 信号与AOF后小鼠的高血压有关。Aim 2检验后AOF的子假说 高血压与PVN中的GPER信号有关。这些研究将使用 包括高分辨率解剖学、神经生理学、体内基因打靶和 单细胞RNA测序方法。