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

• 批准号: 10163278
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163278
• 关键词: Affect; Aging; Alzheimer' 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

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.

先兆子痫（PE）是一种常见的妊娠高血压疾病，会引起明显的母亲和胎儿 全球发病率和死亡率。 PE的后果远远超出了怀孕，并且有关联 患有过度心血管和脑血管疾病的风险过多，包括增加9倍的风险 死于心肌梗塞和中风风险增加4至5倍。 PE女性也癫痫发作很高 敏感性（称为子痫），在癫痫发作和以后会引起相当大的发病率和死亡率 在生活中。重要的是，以前的体育和eclampic妇女（PE女性癫痫发作）的认知和大脑较差 生命之后的萎缩，磁共振成像（MRI）上的白质病变增加了 与认知缺陷和衰落相关。体育和子痫对记忆和认知的影响 表明海马受到不利影响，一个大脑区域在巩固长期的大脑区域 以及短期内存和空间导航。我们以前的研究发现，海马小动脉（HAS）， 在实验性PE的模型中，灌注海马的小脑小动脉较小且僵硬 （EPE）比与轻度认知障碍有关的正常妊娠动物的（EPE）。在 此外，EPE动物缺乏对癫痫发作的高血分反应，这与更大的神经元有关 受伤。因此，该提案的总体目标是研究海马损伤和 PE和ECLAMPSIA期间的认知障碍。该应用程序的总体假设是HA重塑 EPE期间的刚度增加会导致海马损伤，从而促进认知障碍。我们将 因此，研究了EPE中发生重塑和刚度增加的机制以及 防止血管变化会防止认知障碍（AIM 1）。我们还将确定 海马受伤时长时间和复发性癫痫发作，如果防止HA重塑将防止受伤 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持续 （产后几个月）在EPE大鼠（AIM 3）。拟议的研究将对 认知障碍在患有PE的女性中导致认知障碍的机制以及癫痫发作如何不利影响 孕妇大脑。该项目的潜在结果是确定新的治疗目标和策略 预防和/或治疗PE和ECLAMPSIA女性的海马损伤，可以改善 有这种情况的妇女。