Platelet-mediated mechanisms of placental and systemic hypercoagulability in preeclampsia

先兆子痫胎盘和全身高凝状态的血小板介导机制

• 批准号: 10509032
• 负责人: Ana Carolina Palei
• 金额: $ 10.64万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-20 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10509032
• 关键词: Address; Affect; Angiogenic Factor; Animals; Anticoagulants; Apoptosis; Automobile Driving; Blood Circulation; Blood Platelets; Brain Hypoxia-Ischemia; Cells; Chronic; Clinical; Consumption; Cytolysis; Data; Deoxyribonuclease I; Disease; Endoglin; Enzymes; Etiology; Event; Exhibits; Experimental Models; Fetal Growth Retardation; Fibrinolytic Agents; Health; Hemodilution; Hypertension; Hypoxia; In Vitro; Infusion procedures; Injury; Knowledge; Lead; Maternal Mortality; Mediating; Mediator of activation protein; Mentors; Methodology; Mitochondria; Mitochondrial DNA; Mitochondrial Swelling; Modeling; Molecular; Mothers; Organ; Oxides; Pathology; Pathway interactions; Patients; Pattern; Perinatal mortality demographics; Placenta; Placenta Diseases; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Count measurement; Platelet aggregation; Postpartum Period; Pre-Eclampsia; Pregnancy; Premature Birth; Process; Production; Proteinuria; Public Health; Rattus; Reactive Oxygen Species; Research Personnel; Research Project Grants; Risk; Role; Site; Symptoms; Syncytiotrophoblast; System; Testing; Therapeutic; Thrombophilia; Thrombosis; Thrombus; Tissues; Vascular Diseases; Vascular Endothelial Growth Factor Receptor-1; Vesicle; Villous; clinically relevant; clinically significant; effective therapy; experience; extracellular; improved; in vivo; injured; maternal morbidity; maternal risk; mitochondrial dysfunction; novel; novel strategies; novel therapeutics; offspring; perinatal morbidity; pregnancy disorder; pregnant; response; standard of care; thrombotic; training project

PROJECT SUMMARY/ABSTRACT Preeclampsia (PE) remains a significant clinical and public health burden affecting 3-5% of all pregnancies worldwide, and is a leading cause of maternal and perinatal morbidity and mortality. Currently, there is no effective therapy for PE other than delivery. While its etiology is not fully clear, compelling evidence demonstrates that placental hypoxia/ischemia is a key initiating event that triggers the release of anti-angiogenic factors into maternal circulation, such as soluble fms-like tyrosine kinase-1 (sFLT-1) and endoglin (sEng). These placental factors cause systemic vascular dysfunction and ultimately the clinical symptoms of PE. Furthermore, PE is a well-established hypercoagulable state, associated with placental thrombosis as well as increased risk for thrombotic events during and after pregnancy. Hypercoagulability could contribute to exaggerated placental disease and systemic vascular dysfunction in PE. Although increased expression of procoagulant factors and platelet activity along with decreased anticoagulant activity have been implicated in this prothrombotic tendency, the precise mechanism underlying hypercoagulability in PE remain to be fully elucidated. Extracellular mitochondrial DNA (mtDNA), a damage-associated molecular pattern released from hypoxic and/or injured tissue, is known to directly activate platelets, triggering reactive oxygen species overproduction by their mitochondria, which in turn leads to apoptosis and release of additional mtDNA from platelets. This this feed- forward cycle results in escalating platelet activation and hypercoagulability that culminate in thrombosis remote from the initial site of mtDNA release. While placental and maternal mtDNA levels are elevated in PE patients, its role as a mediator of hypercoagulability in the placental and systemic circulation during PE has never been investigated. Moreover, circulating mtDNA can be directly depleted by DNase I treatment, which has been shown to inhibit in vitro and in vivo platelet activation and aggregation. However, DNase I has never been explored as a therapy for PE. To address this knowledge gap, we propose to examine whether mtDNA acts as a driver of hypercoagulability in the placental and systemic circulation during PE, and whether this effect can be mitigated by DNase I treatment using the rat sFLT-1/sEng model of severe PE. Similar to severe preeclamptic patients, the chronic sFLT-1 and sEng infusion into pregnant rats promotes placental pathology, hypertension, reduced platelet counts, and end-organ damage. Parallel ex vivo studies will determine whether sFLT-1, sEng, and placental mtDNA cause platelet activation, mitochondrial dysfunction, and aggregation. Thus, by applying integrative novel approaches, clinically relevant models of PE, and advanced methodologies, we will test the central hypothesis that mtDNA mediates platelet activation, mitochondrial dysfunction, hypercoagulability, and vascular dysfunction in severe PE, and that this pathway is ameliorated by DNase I treatment. Findings generated by these groundbreaking studies could revolutionize the standard of care for PE by identifying a novel class of mtDNA-targeted antithrombotic agents with potential wide applicability to other hypercoagulable states.

项目概要/摘要 先兆子痫 (PE) 仍然是一个重大的临床和公共卫生负担，影响所有妊娠的 3-5% 在世界范围内，它是孕产妇和围产期发病率和死亡率的主要原因。目前，没有 除分娩外，PE 的有效治疗方法。虽然其病因尚不完全清楚，但令人信服的证据表明 胎盘缺氧/缺血是触发抗血管生成因子释放的关键起始事件 母体循环，例如可溶性 fms 样酪氨酸激酶-1 (sFLT-1) 和内皮糖蛋白 (sEng)。这些胎盘 因素导致全身血管功能障碍并最终导致PE的临床症状。此外，PE是一种 已建立的高凝状态，与胎盘血栓形成以及增加的风险有关 妊娠期间和妊娠后的血栓事件。高凝状态可能导致胎盘过度扩张 PE 疾病和全身血管功能障碍。尽管促凝血因子的表达增加 血小板活性以及抗凝活性降低与这种促血栓形成趋势有关， PE 中高凝状态的确切机制仍有待充分阐明。细胞外 线粒体 DNA (mtDNA)，缺氧和/或受伤时释放的一种与损伤相关的分子模式 组织，已知可直接激活血小板，通过其引发活性氧过度产生 线粒体，进而导致细胞凋亡并从血小板中释放额外的 mtDNA。这这饲料—— 正向循环导致血小板活化和高凝状态升级，最终导致远程血栓形成 来自mtDNA释放的初始位点。虽然 PE 患者的胎盘和母体 mtDNA 水平升高， 在PE期间，其作为胎盘和体循环高凝介质的作用从未被研究过。 调查了。此外，循环 mtDNA 可以通过 DNase I 处理直接耗尽，这已被证明 抑制体外和体内血小板活化和聚集。然而，DNase I 从未被探索为 PE 的治疗方法。为了解决这一知识差距，我们建议检查 mtDNA 是否充当驱动因素 PE 期间胎盘和体循环的高凝状态，以及是否可以减轻这种影响 采用 DNase I 治疗严重 PE 大鼠 sFLT-1/sEng 模型。与重度子痫前期患者相似， 长期向怀孕大鼠输注 sFLT-1 和 sEng 可促进胎盘病理、高血压、降低 血小板计数和终末器官损伤。平行离体研究将确定 sFLT-1、sEng 和 胎盘 mtDNA 导致血小板活化、线粒体功能障碍和聚集。因此，通过应用 综合性的新方法、临床相关的 PE 模型和先进的方法，我们将测试 中心假设是 mtDNA 介导血小板活化、线粒体功能障碍、高凝状态和 严重 PE 中的血管功能障碍，并且该途径可通过 DNase I 治疗得到改善。发现 这些开创性的研究产生的结果可能会通过确定一种新颖的方法彻底改变 PE 的护理标准 一类 mtDNA 靶向抗血栓药物，具有广泛适用于其他高凝状态的潜力。