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.
This project will provide a greater understanding of how preeclampsia and eclampsia adversely affect the maternal brain to cause cognitive impairment. The focus on vascular structure and function of deep brain regions, such as the hippocampus that is critical to memory and cognition, as a therapeutic target provides a unique opportunity to treat this condition during pregnancy and its long-term consequences later in life.
