Neurovascular Unit Dysfunction in Women with Severe Preeclampsia

项目概要/摘要 这份职业发展计划的总体目标是让我学习、发展和使用翻译 探讨先兆子痫妇女产后神经血管功能障碍的方法。为了实现这一点， 我将与包括临床和基础科学家在内的多学科导师和合作者团队合作。 先兆子痫（PEC）是一种多系统疾病，发生在3-8%的妊娠中，1，2的特征是： 妊娠后半期的高血压和广泛的内皮功能障碍。PEC增加了 产妇中风的风险高达6倍，1，3和中风占产妇死亡的40-70%， PEC.4，5大多数中风发生在产后的前2周，通常是在妇女出院回家后。 PEC与可逆性脑血管收缩综合征和可逆性后循环综合征有共同的特征。 脑病综合征。8，9这三种情况往往重叠的妇女产后中风， 缺血性卒中、蛛网膜下腔出血和脑出血的主要原因。 我们没有生物标志物来预测哪些患有PEC的女性会发生这些毁灭性的并发症。 PEC导致产后卒中的机制知之甚少。神经血管 单位，包括内皮细胞、平滑肌细胞、周细胞、星形胶质细胞、神经元和细胞外基质 蛋白质，维持血脑屏障的结构完整性。神经血管单位也介导 脑自动调节，或脑血管系统响应于脑缺血而调节脑血流量的能力。 血压的快速变化。人类和动物研究表明， PEC相关脑血管病中神经血管单位的自身调节和血脑屏障特性 10 -15动物研究表明，错误的血管内皮生长因子（VEGF）信号传导和 炎症可能导致PEC相关的神经血管单位功能障碍。10，12，16 我的中心假设是，神经血管单位受到损害，在围产期妇女严重 PEC，由于炎症和VEGF信号传导的中断，导致大脑自动调节功能障碍 和血脑屏障受损在5年的资助期内，我将在 一组80名患有和不患有重度PEC的孕妇。在目标1中，我将使用经颅多普勒和非经颅多普勒。 有创血压监测检测产后脑自动调节功能， 收集血清和脑脊液中VEGF相关蛋白和炎性细胞因子的水平 研究参与者在分娩时。在目标2中，我将培养的人脑内皮细胞暴露于 相同的生物标本，以确定VEGF信号通路在PEC相关血脑中的作用 屏障功能障碍通过这些互补但独立的目标，我希望确定生理和 血清学生物标志物，以确定妇女在产后急性脑血管并发症的高风险。

PROJECT SUMMARY/ABSTRACT The overall goal of this career development proposal is for me to learn, develop and use translational approaches to investigate postpartum neurovascular dysfunction in women with preeclampsia. To achieve this, I will work with a multidisciplinary team of mentors and collaborators including both clinical and basic scientists. Preeclampsia (PEC), a multisystem disorder occurring in 3-8% of pregnancies,1,2 is characterized by hypertension during the second half of pregnancy and widespread endothelial dysfunction. PEC increases the risk of maternal stroke up to 6-fold,1,3 and strokes account for 40-70% of maternal deaths in women with PEC.4,5 Most strokes occur in the first 2 weeks postpartum, often after women have been discharged home.6,7 PEC shares features with the reversible cerebral vasoconstriction syndrome and the posterior reversible encephalopathy syndrome.8,9 These three conditions often overlap in women with postpartum stroke, and are leading causes of ischemic stroke, subarachnoid hemorrhage and intracerebral hemorrhage in this population. We have no biomarkers to predict which women with PEC will develop these devastating complications. The mechanisms by which PEC leads to postpartum stroke are poorly understood. The neurovascular unit, comprising endothelial cells, smooth muscle cells, pericytes, astrocytes, neurons, and extracellular matrix proteins, maintains the structural integrity of the blood-brain barrier. The neurovascular unit also mediates cerebral autoregulation, or the ability of the cerebral vasculature to regulate cerebral blood flow in response to rapid changes in blood pressure. Human and animal studies have implicated abnormalities in both autoregulatory and blood-brain barrier properties of the neurovascular unit in PEC-related cerebrovascular dysfunction.10-15 Animal studies have suggested faulty vascular endothelial growth factor (VEGF) signaling and inflammation may lead to PEC-associated neurovascular unit dysfunction.10,12,16 My central hypothesis is that the neurovascular unit is compromised in peripartum women with severe PEC, due to inflammation and disruptions in VEGF signaling causing both cerebral autoregulatory dysfunction and blood-brain barrier compromise. In the 5-year period of grant support, I will conduct a prospective study in a cohort of 80 pregnant women with and without severe PEC. In Aim 1, I will use transcranial Doppler and non- invasive blood pressure monitoring to test postpartum cerebral autoregulatory function, correlating the results with levels of VEGF-related proteins and inflammatory cytokines in serum and cerebrospinal fluid collected from study participants at the time of delivery. In Aim 2, I will expose cultured human brain endothelial cells to the same biospecimens to determine the role of VEGF signaling pathways in PEC-associated blood-brain barrier dysfunction. Through these complementary but independent aims, I hope to identify physiological and serological biomarkers to identify women at higher risk of postpartum acute cerebrovascular complications.