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: 10622557
• 负责人: Eliza C Miller
• 金额: $ 21.75万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10622557
• 关键词: Acute; Angiogenic Factor; Animals; Astrocytes; Biological Markers; Blood - brain barrier anatomy; Blood Pressure; Blood Pressure Monitors; Blood brain barrier dysfunction; Cephalic; 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; Endothelium; Exposure to; Extracellular Matrix Proteins; Frequencies; Functional disorder; Goals; Grant; Hemorrhage; High Risk Woman; Home; Homeostasis; Human; Hypertension; Immunofluorescence Immunologic; Impairment; In Vitro; Inflammation; Inflammatory; Ischemic Stroke; 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; Serology; Serum; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stroke; Subarachnoid Hemorrhage; Syndrome; System; 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 这份职业发展建议的总体目标是让我学习、开发和使用翻译 研究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增加了 孕妇中风的风险高达6倍、1，3倍，中风占女性孕产妇死亡的40%-70% 大多数中风发生在产后2周内，通常是在妇女出院后。 PEC与可逆性脑血管收缩综合征和后部可逆性脑血管收缩综合征的特征相同 脑病综合征。8，9这三种情况在患有产后中风的妇女中经常重叠，并且 在这一人群中导致缺血性中风、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导致产后中风的机制还知之甚少。神经血管 单位，由内皮细胞、平滑肌细胞、周细胞、星形胶质细胞、神经元和细胞外基质组成 蛋白质，维持血脑屏障的结构完整性。神经血管单位也在 大脑自动调节，或脑血管系统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，这两种疾病都存在异常。 PEC相关脑血管中神经血管单位的自我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)信号转导和 炎症可能导致PEC相关的神经血管单位功能障碍。 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损。 PEC，由于炎症和血管内皮生长因子信号中断导致大脑自动调节功能障碍 和血脑屏障的妥协。在五年的资助期间，我将在 80名患有和不患有严重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 有创血压监测检测产后脑自我调节功能，相关结果 采集血清和脑脊液中血管内皮生长因子相关蛋白和炎性细胞因子水平 在分娩时从研究参与者那里获得。在目标2中，我将培养的人脑内皮细胞暴露于 用相同的生物样品确定血管内皮生长因子信号通路在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 血清生物标记物用于确定产后急性脑血管并发症风险较高的妇女。

项目成果

Ischemic stroke and cerebral venous sinus thrombosis in pregnancy.

• DOI: 10.1016/b978-0-444-64240-0.00001-5
• 发表时间: 2020
• 期刊: Handbook of clinical neurology
• 作者: Roeder HJ;Lopez JR;Miller EC
• 通讯作者: Miller EC

Rural-Urban Differences in Diagnosed Cervical Artery Dissection in New York State.

• DOI: 10.1159/000521204
• 发表时间: 2022
• 期刊: CEREBROVASCULAR DISEASES
• 影响因子: 2.9
• 作者: Hunter, Madeleine Dulany;Kulick, Erin R.;Miller, Eliza;Willey, Joshua;Boehme, Amelia K.;Branas, Charles;Elkind, Mitchell S. V.
• 通讯作者: Elkind, Mitchell S. V.

Reduced-order modeling and analysis of dynamic cerebral autoregulation via diffusion maps.

通过扩散图进行动态大脑自动调节的降阶建模和分析。

• DOI: 10.1088/1361-6579/acc780
• 发表时间: 2023
• 期刊: Physiological measurement
• 影响因子: 3.2
• 作者: DosSantos,KRM;Katsidoniotaki,MI;Miller,EC;Petersen,NH;Marshall,RS;Kougioumtzoglou,IA
• 通讯作者: Kougioumtzoglou,IA

Influenza-Like Illness is Associated with Increased Short-Term Risk of Cervical Artery Dissection.

• DOI: 10.1016/j.jstrokecerebrovasdis.2020.105490
• 发表时间: 2021-02
• 期刊: JOURNAL OF STROKE & CEREBROVASCULAR DISEASES
• 影响因子: 2.5
• 作者: Hunter, Madeleine D.;Moon, Yeseon P.;Miller, Eliza C.;Kulick, Erin R.;Boehme, Amelia K.;Elkind, Mitchell S., V
• 通讯作者: Elkind, Mitchell S., V

Advice for Early Career Clinical Stroke Researchers Applying for National Institutes of Health Funding.

为申请国立卫生研究院资助的早期职业临床中风研究人员提供建议。

• DOI: 10.1161/strokeaha.122.037420
• 发表时间: 2023
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Miller,ElizaC;Pemberton,Victoria
• 通讯作者: Pemberton,Victoria