Placental Ischemia, Hypertension and Hemodyanmics

脑血管改变在子痫前期合并脑血管病变发病机制中的作用 在所有先兆子痫/子痫死亡中，约40%是由事件引起的。对潜在的问题了解甚少 致因机制。几项研究表明，脑血流(CBF)自动调节功能受损 怀孕/先兆子痫是一个主要的潜在因素。我们有令人信服的数据表明缺血胎盘 将影响脑血管功能的因子释放到血液循环中。这些因素包括 细胞因子肿瘤坏死因子-α是一种激活血管紧张素受体1型自身抗体。 Aa)，以及可溶性FMS样酪氨酸激酶(SFlt1)增加，从而损害血管生成原的功能 胎盘生长因子(PlGF)等因子。重要的是，这些因素反映了人类身上发生的变化 在我们的胎盘缺血大鼠模型中也观察到了先兆子痫，这种模型模拟了 先兆子痫的特点。这项研究表明，肿瘤坏死因子-α可以损害脑血管张力和 通过调节细胞内血管平滑肌钙离子([Ca~(2+)]IC)实现脑血流量的自动调节。肿瘤坏死因子-α 也刺激AT1-AA的产生，AT1-AA被认为通过 血管紧张素受体介导的机制。最后，文献中的证据表明，要么AT1- 在这种胎盘缺血模型中，AA或肿瘤坏死因子-α可促进循环sFlt1的增加。SFlt1已被 显示可增加脑血管的通透性，外源性给予PlGF已被证实 在先兆子痫的啮齿动物和非人类灵长类动物模型中都显示出降低高血压的作用。这项建议 将利用大鼠胎盘缺血模型来检验脑部并发症的中心假说 先兆子痫是由缺血胎盘释放的因子(肿瘤坏死因子-α、血管紧张素Ⅱa、可溶性Flt1)引起的。 直接损害脑血管张力和血流自动调节。我们进一步假设，这些因素 血脑屏障通透性增加，再加上脑血流量自我调节受损，导致脑水肿。这 检验假说的目的如下：(1)检验循环产生肿瘤坏死因子-α的假说 通过降低脑血管张力来损害脑血流量的自我调节。(2)。来检验AT1-AA的假设 通过AT1受体介导的机制促进妊娠期受损的CBF自我调节 直接增加血脑屏障通透性。(3)检验假设sFlt1引起的循环增加 胎盘缺血通过增加血脑屏障通透性而导致脑水肿。

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.