Hippocampal arteriole remodeling and brain injury in preeclampsia and eclampsia

子痫前期(PE)是一种常见的妊娠期高血压疾病，可导致严重的母婴疾病 世界范围内的发病率和死亡率。PE的后果远远超出了怀孕的范围，并与 在晚年有过高的心脑血管疾病风险，包括风险增加9倍 死于心肌梗塞，中风的风险增加4到5倍。体育女性的癫痫发病率也很高 易感性(称为子痫)，在癫痫发作期间和后来都会导致相当大的发病率和死亡率 在生活中。重要的是，前PE和子痫妇女(PE妇女癫痫发作)的认知和大脑较差 晚年萎缩，磁共振成像(MRI)阳性的脑白质病变增多 与认知缺陷和衰退有关。PE和子痫对记忆和认知的影响 提示海马体受到不利影响，这是一个在长期高血压的巩固中起关键作用的大脑区域。 以及短期记忆和空间导航。我们之前的研究发现，海马区小动脉(HAS)， 在实验性PE模型中，注入海马区的小脑小动脉更小、更坚硬 (EPE)比正常晚孕动物的EPE要高，这与轻度认知障碍有关。在……里面 此外，EPE动物对癫痫发作缺乏充血反应，这与更大的神经元有关。 受伤。因此，这项建议的总体目标是研究海马区损伤的血管机制和 体育和子痫时的认知损害。这项应用的总体假设是HA重塑 而在EPE期间僵硬的增加会导致海马区损伤，从而促进认知障碍。我们会 因此，研究EPE和IF中HA重塑和僵硬增加的机制 防止血管改变将防止认知障碍(目标1)。我们还将确定 长时间反复发作的海马区损伤，如果阻止HA重塑就能防止损伤 癫痫发作期间(目标2)。最后，我们将确定血管和认知的变化是否会长期存在 (产后数月)EPE大鼠(目标3)。拟议的研究将使人们更了解 女性PE患者认知障碍的发生机制以及癫痫发作如何对 母性大脑。该项目的潜在结果是确定新的治疗目标和战略 预防和/或治疗PE和子痫患者的海马区损伤可改善患者的生活 有这种情况的女性。

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.