Cerebrovascular Abnormalities in Preeclampsia

先兆子痫的脑血管异常

• 批准号: 9478678
• 负责人: Junie Paula Warrington
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9478678
• 关键词: ASIC channel; Acute; Affect; Animal Model; Antibodies; Autoantibodies; Blood - brain barrier anatomy; Blood Pressure; Blood Vessels; Blurred vision; Brain; Brain scan; Caliber; Cerebral Edema; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Cessation of life; Characteristics; Clinical Data; Data; Diagnosis; Drowsiness; Eclampsia; Edema; Event; Fetus; Headache; Homeostasis; Human; Hypertension; Impairment; Ischemia; Laboratories; Lead; Link; Magnetic Resonance Imaging; Mediating; Mentors; Modeling; Morbidity - disease rate; Mothers; Mus; Nausea; Neurologic Symptoms; Organ; Patients; Perfusion; Perinatal mortality demographics; Permeability; Pharmaceutical Preparations; Phase; Placenta; Play; Postpartum Period; Pre-Eclampsia; Predisposition; Pregnancy; Premature Birth; Protein Family; Proteins; Publishing; Rattus; Receptor, Angiotensin, Type 1; Reporting; Research; Risk; Role; Seizures; Smooth Muscle Myocytes; Techniques; Testing; Tissues; Vascular Smooth Muscle; Water; X-Ray Computed Tomography; antenatal; base; cerebral artery; cerebrovascular; clinically relevant; epithelial Na+ channel; fetal; in vivo; maternal morbidity; mechanotransduction; member; perinatal morbidity; pregnant; pressure; protein expression; response; therapeutic target; vascular abnormality

 DESCRIPTION (provided by applicant):PROJECT SUMMARY/ABSTRACT Preeclampsia, the leading cause of premature births and major contributor to maternal and fetal morbidity, affects 5-8% of all pregnancies in the US. Cerebrovascular abnormalities are implicated in 40% of all preeclampsia/eclampsia related deaths; yet the pathophysiological mechanisms involved have not been fully elucidated. The mentored phase of this proposal will test the hypothesis that increases in circulating agonistic antibodies to the angiotensin II Type 1 receptor (AT1-AA) contribute to abnormalities in cerebrovascular function potentially through decreased expression of beta epithelial sodium channel (βENaC). AT1-AAs are increased in preeclamptic patients and induce hypertension when infused in normal pregnant rats. Compelling evidence suggests that the degenerin family of proteins, composed of ENaCs and acid sensing ion channels (ASICs), play a major role in mechanotransduction in vascular smooth muscle cells. These proteins have been shown to mediate the myogenic response, a mechanism that protects the microvessels and subsequent tissue from damage by reducing intraluminal diameter in response to acute increases in blood pressure. Preeclamptic patients and animal models of preeclampsia display impairments in regulating cerebral blood flow which can contribute to cerebral edema and blood-brain barrier disruption. Indeed, magnetic resonance imaging and computed tomography scans of brains of preeclamptic patients demonstrate characteristics of cerebral edema. Additionally, previous research has shown that βENaC is reduced in cerebral arteries isolated from placental ischemic rats that also have impaired myogenic tone, increased blood-brain barrier permeability, and cerebral edema. Because placental ischemic rats have reduced cerebrovascular βENaC expression and impaired myogenic tone, and because ASIC2 and βENaC are key regulators of the myogenic response, in the R00 phase, I propose to determine whether reductions in βENaC and ASIC2 during pregnancy play a role in mediating cerebrovascular abnormalities. I hypothesize that reductions in βENaC and ASIC2 during pregnancy lead to impaired myogenic reactivity of the cerebral blood vessels, impaired cerebral blood flow autoregulation, increased blood-brain barrier permeability and edema, and increased susceptibility to seizures. I will utilize genetically modified mice with reduced βENaC and/ or ASIC2 to determine whether these degenerin proteins are important in maintaining cerebrovascular function during pregnancy.

 描述（由申请人提供）：项目总结/摘要先兆子痫是早产的主要原因，也是孕产妇和胎儿发病的主要原因，影响美国所有妊娠的5-8%。脑血管异常与所有先兆子痫/子痫相关死亡的40%有关;但所涉及的病理生理机制尚未完全阐明。本提案的指导阶段将检验以下假设：血管紧张素II 1型受体（AT 1-AA）的循环激动性抗体增加可能通过β上皮钠通道（βENaC）表达降低导致脑血管功能异常。AT 1-AAs在先兆子痫患者中增加，并在正常妊娠大鼠中注入时引起高血压。令人信服的证据表明，由ENaCs和酸敏感离子通道（ASIC）组成的蛋白质的简并蛋白家族在血管平滑肌细胞中的机械转导中起主要作用。这些蛋白质已被证明介导生肌反应，这是一种通过响应于血压的急性升高而减小管腔内直径来保护微血管和随后的组织免受损伤的机制。先兆子痫患者和先兆子痫的动物模型显示出调节脑血流的障碍，这可导致脑水肿和血脑屏障破坏。事实上，先兆子痫患者大脑的磁共振成像和计算机断层扫描显示了脑水肿的特征。此外，先前的研究表明，从胎盘缺血大鼠分离的脑动脉中βENaC减少，这些大鼠也具有受损的肌原性张力、增加的血脑屏障通透性和脑水肿。由于胎盘缺血大鼠脑血管βENaC表达减少，肌源性张力受损，并且由于ASIC 2和βENaC是肌源性反应的关键调节因子，因此在R 00期，我建议确定妊娠期间βENaC和ASIC 2的减少是否在介导脑血管异常中发挥作用。我推测妊娠期间βENaC和ASIC 2的减少导致脑血管的肌源性反应性受损、脑血流自动调节受损、血脑屏障通透性增加和水肿以及癫痫发作易感性增加。我将利用βENaC和/或ASIC 2减少的转基因小鼠来确定这些变性蛋白在维持妊娠期间脑血管功能方面是否重要。