Preeclampsia and pre-clinical stages of maternal vascular dementia

先兆子痫是一种妊娠期高血压疾病，其后果超出围产期 母亲和孩子的时期。有先兆子痫病史的女性更有可能自我报告 认知抱怨和注意力受损，学习和记忆，这表明 妊娠先兆子痫和母亲的认知功能。最近的大型队列研究表明， 先兆子痫与痴呆的风险增加有关，特别是血管性痴呆， 有先兆子痫病史的孕妇患血管性痴呆的风险比有先兆子痫病史的孕妇高3倍以上。 没有先兆子痫病史的女性目前尚不清楚母体外周神经功能障碍是否 作为先兆子痫的标志的血管系统，延伸到供应大脑的动脉中的功能障碍， 先兆子痫是否会导致母体大脑神经退行性变的早期迹象， 母亲认知障碍拟议的研究将调查胎盘缺血的作用（常见的 先兆子痫妊娠的特征）和Toll样受体-9活性增加（TLR-9;记录于 患有先兆子痫的妇女）在母体痴呆的临床前阶段的发展中的作用。我们假设 胎盘缺血通过激活TLR-9信号传导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 怀孕和产后的认知功能。假设：胎盘缺血损害母体 认知功能和这种损害持续产后。为了验证这一假设，我们将测量产妇 实验结束时的露营依赖性认知行为和短时情景记忆 妊娠期和产后两个月的先兆子痫与胎盘缺血的实验模型。目的 2将确定TLR-9激活对脑神经变性的实验模型中的贡献。 先兆子痫伴胎盘缺血假设：胎盘缺血诱导母体脑炎症 和通过激活TLR-9信号传导的氧化应激。为了验证这一假设，我们将测量氧化 与神经退行性疾病临床前阶段有关的母体脑区域中的应激和细胞因子表达 实验性先兆子痫伴胎盘缺血大鼠的疾病。妊娠大鼠将接受以下处理： 载体或TLR-9抑制剂。目的3将确定TLR-9激活对血管损伤的贡献， 在先兆子痫胎盘缺血的实验模型中供应母体脑的动脉。 假设：实验性先兆子痫大鼠的颈动脉僵硬度增加， 产生活性氧（ROS）和增强血管收缩反应，这些作用是 通过TLR-9信号传导的活化介导。为了验证这一假设，我们将使用大鼠的颈动脉， 目标2成功完成拟议的研究将确定TLR-9刺激的贡献 由妊娠期间胎盘缺血诱导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.