Preeclampsia and pre-clinical stages of maternal vascular dementia

子痫前期是一种妊娠期高血压疾病，其后果超出围产期。 母亲和后代的时期。有先兆子痫病史的女性更有可能自我报告 认知主诉，并损害注意力、学习和记忆，这表明 妊娠合并先兆子痫与母体认知功能最近的大型队列研究表明， 先兆子痫与痴呆症，特别是血管性痴呆症的风险增加有关，因为女性 有先兆子痫病史的人患血管性痴呆的风险是 无先兆子痫病史的妇女。目前尚不清楚母体外周功能障碍 血管系统，这是先兆子痫的标志，延伸到供应大脑和 先兆子痫是否会导致母体大脑中神经变性的早期迹象增加风险 母体认知障碍。拟议的研究将调查胎盘缺血(常见)的作用 妊娠期先兆子痫的特征)和Toll样受体-9活性增加(TLR-9；记录在 先兆子痫妇女)在母体痴呆的临床前阶段的发展中。我们假设 胎盘缺血通过激活TLR-9信号通路诱导母体痴呆的临床前阶段 这种损害在产后持续存在。目的1将确定胎盘缺血对母体的影响 孕期和产后的认知功能。假设：胎盘缺血损害母体 认知功能和这种损害在产后持续存在。为了检验这一假设，我们将测量母体 海马区依赖认知行为与短时背景记忆和情景记忆 妊娠期和产后两个月胎盘缺血先兆子痫的实验模型。目标 2将确定TLR-9的激活在脑神经退行性变中的作用。 先兆子痫合并胎盘缺血。假设：胎盘缺血引起母体脑部炎症 和氧化应激通过激活TLR-9信号通路。为了验证这一假设，我们将测量氧化 神经退行性变临床前阶段母体脑区的应激和细胞因子表达 实验性子痫前期合并胎盘缺血大鼠的疾病。怀孕的大鼠将被用来治疗 车辆或TLR-9抑制剂。AIM 3将确定TLR-9激活在血管损伤中的作用 先兆子痫合并胎盘缺血的实验模型中供血母脑的动脉。 假设：实验性子痫前期大鼠颈动脉僵硬、增厚 产生活性氧簇(ROS)和增强的血管收缩反应，这些效应是 通过激活TLR-9信号而介导。为了验证这一假设，我们将使用大鼠的颈动脉 目标2.拟议研究的成功完成将确定TLR-9刺激的贡献 孕期胎盘缺血导致的母体认知障碍的临床前阶段。

Preeclampsia is a hypertensive disorder of pregnancy with consequences extending beyond the perinatal period for the mother and the offspring. Women a history of preeclampsia are more likely to self-report cognitive complaints and have impaired attention, learning, and memory, suggesting an association between pregnancies with preeclampsia and maternal cognitive function. Recent large cohort studies showed that preeclampsia was associated with increased risk of dementia, particularly vascular dementia, since women with a history of preeclampsia had more than a 3-fold increased risk of vascular dementia compared with women with no history of preeclampsia. It is unknown whether dysfunction of the maternal peripheral vasculature, which is a hallmark of preeclampsia, extends to dysfunction in arteries supplying the brain and whether preeclampsia causes early signs of neurodegeneration in the maternal brain increasing risk of maternal cognitive impairment. The proposed studies will investigate the role of placental ischemia (common feature of pregnancies with preeclampsia) and increased Toll-like receptor-9 activity (TLR-9; documented in women with preeclampsia) in the development of preclinical stages of maternal dementia. We hypothesize that placental ischemia induces preclinical stages of maternal dementia through activation of TLR-9 signaling and this impairment persist postpartum. Aim 1 will determine the effects of a placental ischemia on maternal cognitive function during pregnancy and postpartum. Hypothesis: Placental ischemia impairs maternal cognitive function and this impairment persists postpartum. To test this hypothesis, we will measure maternal hippocampal-dependent cognitive behavior and short-term contextual and episodic memory at the end of gestation and two months postpartum in an experimental model of preeclampsia with placental ischemia. Aim 2 will determine the contribution of TLR-9 activation to brain neurodegeneration in an experimental model of preeclampsia with placental ischemia. Hypothesis: Placental ischemia induces maternal brain inflammation and oxidative stress through activation of TLR-9 signaling. To test this hypothesis, we will measure oxidative stress and cytokine expression in maternal brain regions implicated in pre-clinical stages of neurodegenerative diseases in rats with experimental preeclampsia with placental ischemia. Pregnant rats will be treated with vehicle or a TLR-9 inhibitor. Aim 3 will determine the contribution of TLR-9 activation to vascular impairment in arteries supplying the maternal brain in an experimental model of preeclampsia with placental ischemia. Hypothesis: Carotid arteries from rats with experimental preeclampsia have increased stiffness, increased generation of reactive oxygen species (ROS) and enhanced vasoconstrictor responses and these effects are mediated by activation of TLR-9 signaling. To test this hypothesis, we will use carotid arteries from rats used for Aim 2. Successful completion of the proposed studies will establish the contribution of TLR-9 stimulation induced by placental ischemia during pregnancy to preclinical stages of maternal cognitive impairment.