Impact of estradiol on vascular health and subsequent implications for cognitive aging.

项目3摘要 一个悬而未决的重要问题是，雌激素对大脑和认知的保护作用是否 在疾病期间减弱或逆转，如高血压。我们整个计划项目的目标是 使用健康和不健康衰老的临床前啮齿动物模型来解决这一关键差距 雌激素对女性认知老化的影响。项目3中提出的实验通过以下方式促进了这一目标 雌激素对健康和不健康衰老模型血管健康影响的比较 在概念和方法上对其他研究项目进行补充。我们的总体假设是 心血管疾病改变雌激素受体的特征，扰乱雌激素的整合 分子信号通路与雌激素的心血管效应及其下游 预防阿尔茨海默氏症和血管性痴呆。目标1将确定 心血管疾病对激素治疗的血管反应。这一目标利用了同样的中年人 Jill Daniel博士领导的项目1中的Long-Evans绝经后高血压和认知功能下降大鼠模型 并在我们之前合作出版的基础上再接再厉。目标2将确定改变的雌激素受体 表达会影响对雌激素的反应。这些实验利用转基因的ere-荧光素酶小鼠 缺乏ERα或GPER的小鼠无法了解心血管疾病是如何改变这些信号的 降低雌激素保护作用的途径。目标3将评估高血压对动脉的影响 僵硬对女性认知、树突可塑性和神经血管偶联的影响 抗高血压药为大脑提供了最大的保护。这一目标是与Co- 研究人员里卡多·莫斯塔尼博士利用他的Thy-1小鼠系直接评估了 与认知能力下降有关。成功完成项目3中提出的目标将解决 在我们关于更年期激素治疗影响的知识上的关键空白，使新的 早期检测和预防心血管疾病引起的认知功能下降的方法，并提供 改善更年期激素药理以预防阿尔茨海默病的创新策略 和血管性痴呆症。

Project 3 Summary An unresolved and important question is whether estrogen’s protective effects on the brain and cognition are attenuated or reversed during diseases such as hypertension. The goal of our overall Program Project is to address this critical gap using preclinical rodent models of healthy and unhealthy aging to understand estrogen’s impact on female cognitive aging. The experiments proposed in Project 3 contribute to this goal by comparing the impact of estrogen on vascular health in models of healthy versus unhealthy aging and complement the other Research Projects in both concept and approach. Our overall hypothesis is that cardiovascular disease alters the estrogen receptor profile, disrupting the integration of estrogen’s molecular signaling pathways and attenuating estrogen’s cardiovascular effects and downstream protection from Alzheimer’s disease and vascular dementia. Aim 1 will determine the impact of cardiovascular disease on the vascular response to hormone therapy. This aim utilizes the same middle-aged Long-Evans rat model of postmenopausal hypertension and cognitive decline as Project 1 led by Dr. Jill Daniel and builds upon our previous co-authored publication. Aim 2 will establish whether altered estrogen receptor expression impacts the response to estrogen. These experiments utilize transgenic ERE-luciferase mice along with mice lacking either ERα or GPER to grasp how cardiovascular disease alters each of these signaling pathways to reduce estrogen’s protective effects. Aim 3 will assess the impact of hypertension versus arterial stiffness on female cognition, dendritic plasticity, and neurovascular coupling and determine which antihypertensive provides the greatest protection to the brain. This aim was designed in collaboration with Co- Investigator Dr. Ricardo Mostany and utilizes his Thy-1 mouse line to directly assess central mechanisms that are associated with cognitive decline. The successful completion of the aims proposed in Project 3 will address critical gaps in our knowledge on the impact of menopausal hormone therapy, enable the development of novel methods for early detection and prevention of cardiovascular disease-induced cognitive decline, and provide innovative strategies for improving menopausal hormone pharmacology to protect from Alzheimer’s disease and vascular dementia.