Regulation and role of leptin in preeclampsia

先兆子痫是一种妊娠期高血压疾病，是导致母儿不良妊娠结局的主要原因。 在美国的结果。几十年的临床研究表明，脂肪因子瘦素的水平不适当地 增加，独立于体重，在PE患者。然而，瘦素是否在心血管疾病中发挥作用 PE的胎儿结局未知。我们最近建立了瘦素诱导的PE小鼠模型，其中， 外源性瘦素给药诱导内皮功能障碍的PE的临床特征， 妊娠中晚期给药时，高血压、胎盘线粒体功能障碍和胎儿生长受限 怀孕的老鼠该提案的目标是解决有关刺激的知识方面的关键差距 在PE中上调瘦素，并研究瘦素通过其诱导不利的母体和胎儿的机制， 适应我们的中心假设是sFlt-1诱导PE中的高瘦素血症，这促进了PE的发生。 高血压和胎儿生长受限。胎盘缺血是一个关键的启动 事件并诱导抗血管生成环境，最显著地增加可溶性FMS如酪氨酸激酶-1 （sFlt-1），血管内皮生长因子受体1（VEGFR 1）的可溶形式。我们展示了新的初步 sFlt-1增加人和小鼠的瘦素产生的数据。我们还证明，胎盘 在降低的子宫灌注压（RUPP）小鼠PE模型中诱导的缺血增加了循环 瘦素以及sFlt-1。我们将在目的1中测试胎盘缺血是否通过sFlt-1增加瘦素水平， 介导胎盘缺血诱导的内皮和胎盘功能障碍。在这个目标中，我们建议， RUPP小鼠发生内皮功能障碍、高血压、胎盘线粒体功能障碍和胎儿 生长受限，PE的特征，通过瘦素介导的机制。我们将进一步调查 VEGF的sFlt-1隔离是否减少VEGF受体信号传导并促进PE中的瘦素产生。 其他创新的初步数据表明，内皮瘦素受体激活增加了 妊娠小鼠产生内皮素转换酶-1（ECE-1）和内皮素-1（ET-1）。我们进一步 表明瘦素上调内皮盐皮质激素受体的表达，我们已经发表 降低ECE-1表达。因此，在目标2中，我们将测试瘦素是否通过以下途径诱导PE特征： 内皮ET-1介导的内皮功能障碍。我们将使用内皮盐皮质激素 受体缺失以及内皮瘦素受体敲除小鼠，以确定瘦素是否诱导ET-1 通过这些内皮途径的表达导致妊娠小鼠的PE特征。我们将进一步确定 ECE-1是否诱导血管内皮功能障碍以及ECE-1或ET-1受体拮抗剂 消除瘦素诱导的PE。总的来说，目标1和目标2的结果将大大推动该领域的发展 并将提供临床前证据，如果瘦素在PE中的调节或下游机制， 改善PE患者临床护理的潜在疗法。

Preeclampsia (PE) is a hypertensive disease in pregnancy that is a leading cause of adverse maternal and fetal outcomes in the US. Decades of clinical studies demonstrate that levels of the adipokine leptin inappropriately increase, independent of body mass, in PE patients. However, whether leptin plays a role in the cardiovascular and fetal outcomes of PE is unknown. We recently established a mouse model of leptin-induced PE, in which exogenous leptin administration induces the clinical characteristics of PE in endothelial dysfunction, hypertension, placental mitochondrial dysfunction and fetal growth restriction when given in mid-late gestation pregnant mice. The goal of this proposal is to address a critical gap in knowledge regarding the stimuli upregulating leptin in PE and to investigate mechanisms via which leptin induces adverse maternal and fetal adaptations. Our central hypothesis is that sFlt-1 induces hyperleptinemia in PE, which promotes hypertension and fetal growth restriction via endothelial dysfunction. Placental ischemia is a key initiating event in PE and induces an anti-angiogenic milieu, most notably increasing soluble FMS like tyrosine kinase-1 (sFlt-1), the soluble form of vascular endothelial growth factor receptor 1 (VEGFR1). We show novel preliminary data that sFlt-1 increases leptin production in both humans and mice. We also demonstrate that placental ischemia, induced in the Reduced Uterine Perfusion Pressure (RUPP) mouse model of PE, increases circulating leptin as well as sFlt-1. We will test in Aim 1 whether placental ischemia increases leptin levels via sFlt-1, which mediates placental ischemia-induced endothelial and placental dysfunction. In this Aim, we propose that the RUPP mouse develops endothelial dysfunction, hypertension, placental mitochondrial dysfunction and fetal growth restriction, characteristics of PE, via leptin-mediated mechanisms. We will additionally investigate whether sFlt-1 sequestration of VEGF reduces VEGF receptor signaling and promotes leptin production in PE. Additional innovative preliminary data shows that endothelial leptin receptor activation increases the production of endothelin converting enzyme-1 (ECE-1) and endothelin-1 (ET-1) in pregnant mice. We further demonstrate that leptin upregulates endothelial mineralocorticoid receptor expression, which we have published decreases ECE-1 expression. Therefore, in Aim 2 we will test whether leptin induces PE characteristics via endothelial ET-1-mediated endothelial dysfunction. We will utilize mice with endothelial mineralocorticoid receptor deletion as well as endothelial leptin receptor knockout mice to determine whether leptin-induced ET-1 expression by these endothelial pathways leads to PE characteristics in pregnant mice. We will further determine whether ECE-1 induces vascular endothelial dysfunction and whether ECE-1 or ET-1 receptor antagonism ablates leptin-induced PE. Collectively, the results of Aim 1 and 2 will significantly move forward the field of leptin in PE and will give preclinical evidence if regulatory or downstream mechanisms of leptin in PE are potential therapeutics to improve clinical care of PE patients.