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.

子痫前期(PE)是一种妊娠期高血压疾病，是造成母婴不利的主要原因 在美国的结果。数十年的临床研究表明，脂肪因子瘦素的水平不适当 在PE患者中，增加，与体重无关。然而，瘦素是否在心血管疾病中发挥作用 而PE的胎儿结局尚不清楚。我们最近建立了瘦素诱导的小鼠PE模型，其中 外源性瘦素治疗导致内皮功能障碍的PE的临床特征 妊娠中晚期服用高血压、胎盘线粒体功能障碍和胎儿生长受限 怀孕的老鼠。这项建议的目标是解决有关刺激的知识的严重差距。 上调瘦素在PE中的表达及探讨瘦素诱导不良母婴发生的机制 改编。我们的中心假设是sFlt-1诱导了PE中的高瘦素血症，从而促进了 高血压和通过内皮功能障碍导致的胎儿生长受限。胎盘缺血是一个关键的启动因素 事件并诱导抗血管生成环境，最显著的是增加可溶性FMS，如酪氨酸激酶-1 (sFlt-1)，血管内皮生长因子受体1(VEGFR1)的可溶性形式。我们展示了新奇的初步内容 数据表明，sFlt-1增加了人类和小鼠的瘦素生成。我们还证明了胎盘 在降低子宫灌流压(RUPP)的PE小鼠模型中诱导的缺血增加循环 瘦素和sFlt-1。我们将在Aim 1中测试胎盘缺血是否通过sFlt-1增加瘦素水平， 调节胎盘缺血引起的内皮功能障碍和胎盘功能障碍。为了达到这个目的，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。我们还将进一步调查 SFlt-1抑制血管内皮细胞生长因子是否减少血管内皮生长因子受体信号转导，促进瘦素的产生。 更多创新的初步数据显示，内皮瘦素受体的激活增加了 妊娠小鼠体内内皮素转换酶-1和内皮素-1的产生。我们进一步 证明瘦素上调内皮盐皮质激素受体的表达，我们已经发表了这篇文章 减少ECE1的表达。因此，在目标2中，我们将测试瘦素是否通过 内皮细胞ET-1介导的内皮功能障碍。我们将利用血管内皮细胞矿物皮质激素的小鼠 瘦素受体缺失以及内皮细胞瘦素受体敲除小鼠判断瘦素是否诱导ET-1 这些内皮细胞途径的表达导致了怀孕小鼠的PE特征。我们将进一步确定 ECE1是否导致血管内皮功能障碍及ECE1或ET-1受体拮抗作用 消融瘦素诱导的PE。总的来说，目标1和目标2的结果将显著推动这一领域的发展 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。