Placental Ischemia, Hypertension and Hemodyanmics

胎盘缺血、高血压和血流动力学

基本信息

批准号：
9899296
负责人：
Heather A Drummond
金额：
$ 43.68万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899296
关键词：
Affect Angiogenic Factor Angiotensin II Angiotensin Receptor Animal Model Attenuated Autoantibodies Biochemical Blood Circulation Blood Vessels Blood flow Blurred vision Brain Calcium Calcium-Activated Potassium Channel Cerebral Edema Cerebrovascular Circulation Cerebrovascular Disorders Cerebrum Cessation of life Characteristics Chronic Clinical Coupled Data Disease Drowsiness Eclampsia Edema Encephalopathies Event Experimental Models Goals Grant Headache Homeostasis Human Hypertension Impairment Infusion procedures Injury to Kidney Ischemia Knowledge Lead Link Literature Mediating Methods Modeling Nausea Neurologic Symptoms PGF gene Pathogenesis Patients Peptides Physiological Placenta Play Positioning Attribute Pre-Eclampsia Pregnancy Production Publishing Rattus Receptor Activation Receptor, Angiotensin, Type 1 Renal function Reporting Research Rodent Role Seizures TNF gene Testing Vascular Endothelial Growth Factor Receptor-1 Vascular Permeabilities Vascular Smooth Muscle Woman Work base blood-brain barrier permeabilization cerebrovascular clinical predictors cytokine human data improved outcome mortality new therapeutic target nonhuman primate pregnant preservation prevent receptor receptor sensitivity release factor vascular abnormality

项目摘要

Cerebral vascular changes play a significant role in the pathogenesis of preeclampsia with cerebrovascular events contributing to ~40% of all preeclampsia/eclampsia deaths. Little is understood about the underlying causative mechanisms. Several studies suggest that impaired cerebral blood flow (CBF) autoregulation during pregnancy/preeclampsia is a major underlying factor. We have compelling data that the ischemic placenta releases factors into the circulation that can impact cerebral vascular function. These factors include the cytokine tumor necrosis factor alpha (TNF-α), an activating angiotensin receptor type 1 autoantibody (AT1- aa), and an increase in soluble fms like tyrosine kinase (sFlt1) that impairs the function of proangiogenic factors like placental growth factor (PlGF). Importantly, these factors mirror changes that occur in human preeclampsia and are also observed in our experimental rat model of placental ischemia that mimics the characteristics of preeclampsia. This grant proposes that TNF-α can impair cerebral vascular tone and cerebral blood flow autoregulation by regulating intracellular vascular smooth muscle calcium ([Ca2+ ]IC). TNF-α also stimulates the production of the AT1-aa which is proposed to impair cerebral vascular function through and angiotensin receptor mediated mechanism. Finally, evidence in the literature shows that either the AT1- aa or TNF-α can promote an increase in circulating sFlt1 in this model of placental ischemia. sFlt1 has been shown to increase vascular permeability in the brain, and exogenous administration of the PlGF has been shown to attenuate hypertension in both rodent and nonhuman primate models of preeclampsia. This proposal will utilize the rat model of placental ischemia to test the central hypothesis that cerebral complications of preeclampsia are caused by the release of factors from the ischemic placenta (TNF-α, AT1aa, sFlt1) that directly impair cerebral vascular tone and blood flow autoregulation. We further hypothesize that these factors increase BBB permeability, which together with impaired CBF autoregulation leads to cerebral edema. This hypothesis will be tested in the following aims: (1) To test the hypothesis that circulating TNF-α production impairs CBF autoregulation by reducing cerebral vascular tone. (2). To test the hypothesis that the AT1-aa promotes impaired CBF autoregulation during pregnancy through an AT1 receptor mediated mechanism and directly increases BBB permeability. (3) To test the hypothesis that increased circulating sFlt1 caused by placental ischemia contributes to cerebral edema by increasing blood brain barrier permeability.

脑血管改变在子痫前期合并脑血管病的发病机制中起重要作用导致约 40% 的先兆子痫/子痫死亡的事件对潜在的原因知之甚少。一些研究表明，脑血流量（CBF）的自动调节受损。我们有令人信服的数据表明，胎盘缺血是一个主要的潜在因素。将可影响脑血管功能的因素释放到循环中。细胞因子肿瘤坏死因子 α (TNF-α)，一种激活型血管紧张素受体 1 型自身抗体 (AT1- aa)，以及酪氨酸激酶 (sFlt1) 等可溶性 fms 的增加，从而损害促血管生成的功能重要的是，这些因素反映了人类发生的变化。先兆子痫，在我们模拟胎盘缺血的实验性大鼠模型中也观察到该资助提出 TNF-α 可以损害脑血管张力和通过调节细胞内血管平滑肌钙（[Ca2+]IC）实现脑血流自动调节。还刺激 AT1-aa 的产生，推测 AT1-aa 会通过以下方式损害脑血管功能最后，文献证据表明 AT1- 介导的机制。在这种胎盘缺血模型中，aa 或 TNF-α 可以促进循环 sFlt1 的增加。研究表明，外源性给予 PlGF 可以增加大脑血管通透性在先兆子痫的啮齿动物和非人类灵长类动物模型中显示可以减轻高血压。将利用胎盘缺血的大鼠模型来检验以下中心假设：先兆子痫是由缺血胎盘释放因子（TNF-α、AT1aa、sFlt1）引起的，这些因子我们进一步发现这些因素直接损害脑血管张力和血流自动调节。血脑屏障通透性增加，加上脑血流量自动调节受损，导致脑水肿。假设将通过以下目的进行检验： (1) 检验循环中 TNF-α 产生的假设通过降低脑血管张力来损害 CBF 自身调节 (2)。通过 AT1 受体介导的机制促进妊娠期间受损的 CBF 自动调节， (3) 检验循环 sFlt1 增加的假设胎盘缺血通过增加血脑屏障通透性导致脑水肿。