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.

项目摘要/摘要 子痫前期(PE)仍然是一个重大的临床和公共卫生负担，影响到所有妊娠的3%-5% 在全世界范围内，是孕产妇和围产儿发病率和死亡率的主要原因。目前，没有 除分娩外，对PE的有效治疗。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/缺血是一个关键的启动事件，触发抗血管生成因子释放到 母体循环，如可溶性FMS样酪氨酸激酶-1(sFlt-1)和内啡肽(Seng)。这些胎盘 各种因素导致全身血管功能障碍，最终导致PE的临床症状。此外，PE是一种 公认的高凝状态，与胎盘血栓形成相关，并增加了 妊娠期间和怀孕后的血栓事件。高凝状态可能导致胎盘夸大 PE中的疾病和全身血管功能障碍。虽然促凝血因子和凝血因子的表达增加 血小板活性和抗凝活性降低与这种血栓前倾向有关， PE高凝状态的确切机制仍未完全阐明。胞外 线粒体DNA(MtDNA)，一种与缺氧和/或损伤释放的损伤相关的分子模式 组织，已知可直接激活血小板，通过它们的 线粒体，进而导致细胞凋亡和从血小板释放额外的mtDNA。这是这条新闻- 前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 从线粒体DNA释放的初始位置。虽然胎盘和母亲的线粒体DNA水平在PE患者中升高， 在PE期间，它作为胎盘和体循环中高凝状态的中介物的作用从来没有 调查过了。此外，循环中的mtdna可被dna i处理直接耗尽，这已被证明。 抑制体外和体内的血小板活化和聚集。然而，DNase I从未被探索为 一种治疗体育的方法。为了解决这一知识鸿沟，我们建议研究mtDNA是否作为一种驱动因素 PE时胎盘和体循环中的高凝状态及其能否减轻 用DNase I治疗大鼠sFlt-1/Seng重症PE模型。类似于重度先兆子痫患者， SFlt-1和Seng对妊娠大鼠胎盘病理的促进作用 血小板计数和终末器官损伤。平行的体外研究将确定sFlt-1、Seng和 胎盘线粒体DNA可引起血小板活化、线粒体功能障碍和聚集。因此，通过应用 综合的新方法、临床相关的PE模型和先进的方法，我们将测试 中心假设线粒体DNA介导了血小板活化、线粒体功能障碍、高凝状态以及 严重PE中的血管功能障碍，这一途径可通过DNase I治疗得到改善。发现 由这些开创性的研究产生的可能通过识别一种新的 一类以线粒体DNA为靶点的抗血栓药物，具有潜在的广泛应用于其他高凝状态。