Cerebrovascular Abnormalities in Preeclampsia

 描述(由申请人提供)：项目摘要/摘要先兆子痫是早产的主要原因，也是导致母婴发病率的主要因素，在美国影响所有怀孕的5%-8%。在所有与子痫前期/子痫相关的死亡中，40%与脑血管异常有关；然而，涉及的病理生理机制尚未完全阐明。这项提案的指导阶段将检验这一假设，即循环中血管紧张素II1型受体(AT1-AA)激动型抗体的增加可能通过降低β上皮钠通道(βENaC)的表达而导致脑血管功能异常。AT1-AAs在子痫前期患者中增加，并在正常妊娠大鼠输注时引起高血压。令人信服的证据表明，由ENaCs和酸敏感离子通道(ASICs)组成的退行性蛋白家族在血管平滑肌细胞的机械转导中发挥着重要作用。这些蛋白质已被证明介导了肌源性反应，这是一种通过缩小管腔内直径来保护微血管和随后的组织免受损害的机制，以应对血压的急剧上升。子痫前期患者和先兆子痫动物模型在调节脑血流方面表现出障碍，这可能导致脑水肿和血脑屏障破坏。事实上，对先兆子痫患者的大脑进行的磁共振成像和计算机断层扫描显示出脑水肿的特征。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，这些大鼠也有肌源性张力受损、血脑屏障通透性增加和脑水肿。由于胎盘缺血大鼠脑血管βENaC表达减少，肌源性张力受损，而且ASIC2和βENaC是肌源性反应的关键调节因子，在R00阶段，我建议确定妊娠期βENaC和ASIC2的减少是否在调节脑血管异常中发挥作用。我推测，妊娠期β、ENaC和ASIC2的减少会导致脑血管的肌源性反应性受损，大脑血流自动调节受损，血脑屏障通透性和水肿增加，并增加对癫痫的易感性。我将利用β、ENaC和/或ASIC2降低的转基因小鼠来确定这些退行性蛋白是否对维持怀孕期间的脑血管功能重要。

 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.