Neurovascular Unit Dysfunction in Women with Severe Preeclampsia

严重先兆子痫女性的神经血管单元功能障碍

基本信息

批准号：
10186050
负责人：
Eliza C Miller
金额：
$ 10.62万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10186050
关键词：
Acute Angiogenic Factor Animals Astrocytes Biological Markers Blood - brain barrier anatomy Blood Pressure Blood Pressure Monitors Cerebral Edema Cerebral hemisphere hemorrhage Cerebrospinal Fluid Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cerebrum Clinical Cohort Studies Complex Development Diffusion Disease Electrical Resistance Encephalopathies Endothelial Cells Exposure to Extracellular Matrix Proteins Frequencies Functional disorder Goals Grant Hemorrhage High Risk Woman Home environment Homeostasis Human Hypertension Immunofluorescence Immunologic Impairment In Vitro Inflammation Inflammatory Ischemic Stroke Lead Learning Maternal Mortality Measurement Measures Mediating Mentors Methods Neurologic Neurons Participant Pathogenesis Pericytes Perinatal Physiological Play Population Postpartum Period Postpartum Women Pre-Eclampsia Pregnancy Pregnant Women Prenatal Diagnosis Property Prospective Studies Proteins Risk Role Scientist Screening procedure Serological Serum Signal Pathway Signal Transduction Smooth Muscle Myocytes Stroke Structure Subarachnoid Hemorrhage Syndrome TNFSF15 gene Testing Tight Junctions Time Tracer Tyrosine Kinase Inhibitor Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Vasogenic Cerebral Edema Vasospasm Western Blotting Woman Work blood-brain barrier permeabilization brain endothelial cell career development cerebral arteriopathy cerebrovascular cohort cytokine endothelial dysfunction excitotoxicity high risk in vivo maternal risk multidisciplinary neurovascular neurovascular unit response stroke risk translational approach vasoconstriction

项目摘要

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.

项目概要/摘要这个职业发展建议的总体目标是让我学习、发展和使用翻译研究先兆子痫女性产后神经血管功能障碍的方法。为了实现这一目标，我将与一个由导师和合作者组成的多学科团队合作，其中包括临床和基础科学家。先兆子痫 (PEC) 是一种多系统疾病，发生在 3-8% 的妊娠中，1,2 的特点是妊娠后半期高血压和广泛的内皮功能障碍。 PEC 增加孕产妇中风的风险高达 6 倍,1,3 并且中风占患有以下疾病的妇女孕产妇死亡的 40-70% PEC.4,5 大多数中风发生在产后前 2 周，通常是在妇女出院回家后。6,7 PEC 与可逆性脑血管收缩综合征和后可逆性脑血管收缩综合征具有共同特征脑病综合征。8,9 这三种情况在患有产后中风的女性中经常重叠，并且该人群中缺血性中风、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 的女性会出现这些毁灭性的并发症。 PEC 导致产后卒中的机制尚不清楚。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。神经血管单位还介导脑自动调节，或脑血管系统调节脑血流量的能力血压快速变化。人类和动物研究都表明两者存在异常 PEC相关脑血管中神经血管单元的自动调节和血脑屏障特性 10-15 动物研究表明，血管内皮生长因子 (VEGF) 信号传导存在缺陷，炎症可能导致 PEC 相关神经血管单元功能障碍。10,12,16 我的中心假设是，患有严重疾病的围产期妇女的神经血管单位受到损害 PEC，由于炎症和 VEGF 信号传导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，我将进行一项前瞻性研究一项由 80 名患有或不患有严重 PEC 的孕妇组成的队列。在目标 1 中，我将使用经颅多普勒和非有创血压监测测试产后脑自动调节功能，并将结果关联起来收集血清和脑脊液中 VEGF 相关蛋白和炎症细胞因子的水平来自研究参与者在分娩时的情况。在目标 2 中，我将把培养的人脑内皮细胞暴露于使用相同的生物样本来确定 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可识别产后急性脑血管并发症风险较高的女性。