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Hippocampal arteriole remodeling and brain injury in preeclampsia and eclampsia

先兆子痫和子痫的海马小动脉重塑和脑损伤

基本信息

批准号：
10404042
负责人：
Marilyn J Cipolla
金额：
$ 39万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10404042
关键词：
Affect Aging Alzheimer&apos s Disease Animals Arteries Behavioral Blood Vessels Blood flow Brain Brain Injuries Brain region Cardiovascular Diseases Cell Death Cerebrovascular Circulation Cerebrovascular Disorders Cognition Cognitive deficits Development Eclampsia Experimental Models Functional disorder Glutamates Goals Heart Hippocampus (Brain)Hyperactivity Hyperemia Hyperlipidemia Hypertension Hypoxia Immunohistochemistry Impaired cognition Impairment Injury Lead Lesion Life Link Magnetic Resonance Imaging Maternal Mortality Measures Memory Microcirculation Morbidity - disease rate Myocardial Infarction Nature Neuronal Injury Neurons Neurotransmitters Onset of illness Outcome Oxidative Stress Oxygen Pathway interactions Peripheral Physiologic pulse Postpartum Period Pre-Eclampsia Predisposition Pregnancy Rattus Recurrence Risk Role Seizures Structure Testing Travel Trees Vascular Diseases Vascular blood supply Vascular remodeling Vascular resistance Woman arteriole cerebral atrophy cognitive change cognitive testing disorder risk early onset endothelial dysfunction excitotoxicity experimental study fetal improved in vivo ischemic injury long short term memory long term memory maternal morbidity mild cognitive impairment morris water maze mortality new therapeutic target novel object recognition oxidized low density lipoprotein parenchymal arterioles pregnancy disorder pregnant pressure prevent response stroke risk therapeutic target tissue oxygenation way finding white matter

项目摘要

Preeclampsia (PE) is a common hypertensive disorder of pregnancy that causes significant maternal and fetal morbidity and mortality worldwide. The consequences of PE extend far beyond pregnancy and are associated with excessive cardiovascular and cerebrovascular disease risk later in life, including a 9-fold increased risk of dying from myocardial infarction and a 4- to 5-fold increased risk of stroke. PE women also have high seizure susceptibility (called eclampsia) that causes considerable morbidity and mortality both during seizure and later in life. Importantly, former PE and eclamptic women (seizure in a PE woman) have poorer cognition and brain atrophy later in life, with increased white matter lesions on magnetic resonance imaging (MRI) that positively correlate with cognitive defects and decline. The effect of PE and eclampsia on memory and cognition suggests the hippocampus is adversely affected, a brain region that has a critical role in consolidation of long- and short-term memory and spatial navigation. Our previous studies found that hippocampal arterioles (HAs), small brain arterioles that perfuse the hippocampus, were smaller and stiffer in a model of experimental PE (ePE) than HAs from normal late-pregnant animals that was associated with mild cognitive impairment. In addition, ePE animals lacked a hyperemic response to seizure that was associated with greater neuronal injury. Thus, the overall goal of this proposal is to investigate vascular mechanisms of hippocampal injury and cognitive impairment during PE and eclampsia. The overall hypothesis of this application is that HA remodeling and increased stiffness during ePE causes hippocampal injury that promotes cognitive impairment. We will therefore investigate mechanisms by which HA remodeling and increased stiffness occurs in ePE and if preventing the vascular changes will prevent cognitive impairment (Aim 1). We will also determine the effect of prolonged and recurrent seizure on hippocampal injury and if preventing HA remodeling will prevent injury during seizure (Aim 2). And lastly, we will determine if the vascular and cognitive changes persist long-term (months postpartum) in ePE rats (Aim 3). The proposed studies will provide a greater understanding of the mechanisms by which cognitive impairment occurs in women with PE and how seizure adversely affects the maternal brain. The potential outcome of this project is identifying new therapeutic targets and strategies for preventing and/or treating hippocampal injury in women with PE and eclampsia that could improve the lives of women with this condition.

子痫前期是一种常见的妊娠期高血压疾病，发病率和死亡率。PE的后果远远超出妊娠期，在以后的生活中有过度的心血管和脑血管疾病风险，包括9倍的风险增加，死于心肌梗死和中风的风险增加4到5倍。PE女性也有高癫痫发作易感性（称为子痫），在癫痫发作期间和之后都引起相当大的发病率和死亡率生活中重要的是，前PE和子痫妇女（PE妇女癫痫发作）的认知和大脑功能较差，在以后的生活中萎缩，磁共振成像（MRI）显示白色病变增加，与认知缺陷和衰退有关。PE和子痫对记忆和认知的影响这表明海马体受到了不利的影响，海马体是一个在巩固长时间记忆中起关键作用的大脑区域，以及短期记忆和空间导航。我们以前的研究发现，海马小动脉（HAs），在实验性PE模型中，灌注海马的小脑动脉更小，更硬 (ePE)与轻度认知障碍相关的正常晚期妊娠动物的HA相比。在此外，ePE动物缺乏对癫痫发作的充血反应，这与更大的神经元损伤因此，本研究的总体目标是研究海马损伤的血管机制， PE和子痫期间的认知障碍。本申请的总体假设是HA重塑 ePE期间增加的僵硬会导致海马损伤，从而促进认知障碍。我们将因此，研究ePE中HA重塑和刚度增加的机制，防止血管变化将防止认知损害（目标1）。我们还将确定如果阻止HA重塑，则可防止损伤在癫痫发作期间（目标2）。最后，我们将确定血管和认知变化是否会长期持续（产后月数）（目的3）。拟议的研究将使人们更好地了解 PE女性认知功能障碍的发生机制以及癫痫发作如何对母亲的大脑该项目的潜在成果是确定新的治疗靶点和策略，预防和/或治疗患有PE和子痫的女性的海马损伤，有这种情况的女人。