Regulation and role of leptin in preeclampsia

瘦素在先兆子痫中的调节和作用

• 批准号: 10719484
• 负责人: Jessica L. Faulkner
• 金额: $ 53.07万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719484
• 关键词: Ablation; Address; Adipose tissue; Angiogenesis Inhibitors; Arteries; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cells; Characteristics; Chronic; Clinical; Clinical Research; Data; Disease; Elements; Endocrine; Endothelial Cells; Endothelial Growth Factors Receptor; Endothelin A Receptor; Endothelin-1; Endothelin-converting enzyme 1; Endothelium; Event; Female; Fetal Growth Retardation; Functional disorder; Future; Goals; Hormones; Human; Hypertension; Ischemia; Knockout Mice; Knowledge; Leptin; Link; Low Birth Weight Infant; Mediating; Mineralocorticoid Receptor; Mitochondria; Modeling; Mothers; Mus; Obesity; Outcome; Pathway interactions; Patients; Perfusion; Placenta; Plasma; Pre-Eclampsia; Pregnancy; Pregnant Women; Production; Publishing; Receptor Activation; Receptor Signaling; Regulation; Reporting; Research; Resistance; Role; Severities; Stimulus; Symptoms; System; Testing; Therapeutic; Time; Tissues; Uterus; Vascular Diseases; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; adipokines; antagonist; cardiometabolic risk; clinical care; cohort; endothelial dysfunction; fetal; improved; innovation; leptin receptor; mitochondrial dysfunction; mouse model; novel; offspring; pre-clinical; preclinical study; pregnancy disorder; pregnant; pressure; receptor; receptor expression; tool; vascular endothelial dysfunction

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.

先兆子痫（PE）是一种妊娠期高血压疾病，是母婴不良的主要原因 在美国取得的成果。数十年的临床研究表明，脂肪因子瘦素的水平不适当 PE 患者的增加与体重无关。然而，瘦素是否在心血管中发挥作用？ PE 的胎儿结局尚不清楚。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中 PE 的临床特征， 妊娠中晚期服用时会出现高血压、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 上调 PE 中的瘦素并研究瘦素诱导母体和胎儿不良的机制 适应。我们的中心假设是 sFlt-1 在 PE 中诱导高瘦素血症，从而促进 通过内皮功能障碍导致高血压和胎儿生长受限。胎盘缺血是关键的始动 PE 中的事件并诱导抗血管生成环境，最显着的是增加可溶性 FMS，如酪氨酸激酶-1 (sFlt-1)，血管内皮生长因子受体 1 (VEGFR1) 的可溶形式。公开新颖的初步 数据表明 sFlt-1 可以增加人类和小鼠瘦素的产生。我们还证明胎盘 PE 子宫灌注压降低 (RUPP) 小鼠模型中诱导的缺血会增加循环 瘦素以及 sFlt-1。我们将在目标 1 中测试胎盘缺血是否通过 sFlt-1 增加瘦素水平，这 介导胎盘缺血引起的内皮和胎盘功能障碍。在这一目标中，我们建议 RUPP 小鼠出现内皮功能障碍、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。我们将另外调查 sFlt-1 隔离 VEGF 是否会减少 VEGF 受体信号传导并促进 PE 中瘦素的产生。 其他创新的初步数据表明，内皮瘦素受体激活可增加 怀孕小鼠内皮素转换酶-1 (ECE-1) 和内皮素-1 (ET-1) 的产生。我们进一步 证明瘦素上调内皮盐皮质激素受体表达，我们已发表 降低 ECE-1 表达。因此，在目标 2 中，我们将通过以下方式测试瘦素是否诱导 PE 特征： 内皮 ET-1 介导的内皮功能障碍。我们将使用具有内皮盐皮质激素的小鼠 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 这些内皮途径的表达导致怀孕小鼠出现 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受体是否拮抗 消除瘦素诱导的 PE。总的来说，目标 1 和 2 的结果将显着推动该领域的发展 瘦素在 PE 中的作用，如果瘦素在 PE 中的调节或下游机制得到​​证实，将提供临床前证据 改善PE患者临床护理的潜在疗法。