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

项目3摘要 一个尚未解决的重要问题是雌激素对大脑和认知的保护作用是否 在高血压等疾病期间减弱或逆转。我们整个项目的目标是 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中提出的实验有助于实现这一目标， 比较雌激素对健康与不健康衰老模型中血管健康的影响， 在概念和方法上补充其他研究项目。我们的总体假设是 心血管疾病改变了雌激素受体的分布，破坏了雌激素的整合， 分子信号通路和减弱雌激素的心血管效应和下游 预防阿尔茨海默病和血管性痴呆。目标1将决定 心血管疾病对血管激素治疗的反应。这一目标利用同样的中年 由Jill丹尼尔博士领导的项目1绝经后高血压和认知能力下降的Long-Evans大鼠模型 并建立在我们以前共同撰写的出版物上。目的2将确定是否改变雌激素受体 表达影响对雌激素的反应。这些实验利用转基因ERE-荧光素酶小鼠沿着 用缺乏ERα或GPER的小鼠来了解心血管疾病如何改变这些信号传导 减少雌激素保护作用的途径。目标3将评估高血压与动脉粥样硬化的影响， 刚性对女性认知、树突可塑性和神经血管耦合的影响，并决定 抗高血压药对大脑有最大的保护作用。这一目标是与合作伙伴共同设计的， 研究者Ricardo Mostany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 我们对绝经期激素治疗影响的认识存在重大差距， 用于早期检测和预防心血管疾病引起的认知衰退的方法，并提供 改善更年期激素药理学以预防阿尔茨海默病的创新策略 和血管性痴呆

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.