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

• 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
• 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

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.

项目摘要/摘要 这项职业发展建议的总体目标是我学习，开发和使用翻译 研究前启示性女性的神经血管产后神经血管功能障碍的方法。为此， 我将与包括临床和基础科学家在内的跨学科团队和合作者组成的团队。 先兆子痫（PEC），一种在3-8％的怀孕中发生的多系统疾病，1,2的特征是 怀孕后半段的高血压和广泛的内皮功能障碍。 PEC增加了 孕产妇中风的风险高达6倍，1,3和中风的风险占妇女的孕产妇死亡的40-70％ PEC.4,5大多数中风发生在产后的头两周，通常是在妇女出院后。6,7 PEC与可逆的脑血管收缩综合征和后验可逆分享功能 脑病综合征。8,9这三个疾病在产后中风的女性经常重叠，并且是 该人群中缺血性中风，蛛网膜下腔出血和脑内出血的主要原因。 我们没有生物标志物可以预测哪些PEC女性将发展这些毁灭性的并发症。 PEC导致产后中风的机制知之甚少。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。神经血管单元也介导 脑自动调节，或脑脉管系统调节大脑血流的能力。 血压的快速变化。人类和动物研究都暗示了这两者的异常 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 功能障碍。10-15动物研究表明血管内皮生长因子（VEGF）信号和 炎症可能导致PEC相关的神经血管单元功能障碍。10,12,16 我的中心假设是，神经血管单元在严重的围围妇女中受到损害 PEC，由于炎症和VEGF信号传导的干扰，导致两个大脑自调功能障碍 和血脑屏障妥协。在5年的赠款支持期间，我将进行一项前瞻性研究 有和没有严重PEC的80名孕妇组成的队列。在AIM 1中，我将使用经颅多普勒和非 - 侵入性血压监测以测试产后大脑自调功能，与结果相关 收集的血清和脑脊液中与VEGF相关的蛋白质水平和炎性细胞因子水平 从分娩时的研究参与者。在AIM 2中，我将使培养的人脑内皮细胞暴露于 相同的生物测量确定VEGF信号通路在PEC相关血脑中的作用 障碍障碍。通过这些互补但独立的目标，我希望确定生理和 血清学生物标志物识别出产后急性脑血管并发症风险较高的女性。