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

基本信息

批准号：
10686921
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
项目类别：
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/10686921
关键词：
Address Affect Angiogenesis Inhibitors Angiogenic Factor Animals Anticoagulants Apoptosis Automobile Driving Blood Platelets Brain Hypoxia-Ischemia Cell secretion Cells Chronic Circulation 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 Mentors Methodology Mitochondria Mitochondrial DNA Mitochondrial Swelling Modeling Molecular Mothers Organ 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 particle perinatal morbidity post pregnancy pregnancy disorder pregnant response standard of care thrombotic training project

项目摘要

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）仍然是临床和公共卫生负担，影响了所有怀孕的3-5％全球，是孕产妇和围产期发病率和死亡率的主要原因。目前，没有有效的PE疗法以外的其他疗法。尽管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，可触发抗血管生成因子的释放孕产妇循环，例如可溶性FMS样酪氨酸激酶-1（SFLT-1）和恩格林（Seng）。这些胎盘导致全身性血管功能障碍，最终导致PE的临床症状。此外，PE是公认的超凝状态，与胎盘血栓形成有关，并增加怀孕期间和之后的血栓性事件。高凝性可能导致夸大的胎盘 PE中的疾病和全身血管功能障碍。虽然提高了凝聚因子的表达和血小板活性以及抗凝活性降低已与这种促血栓性趋势有关 PE中的高凝性的确切机制尚待完全阐明。细胞外线粒体DNA（mtDNA），一种由缺氧和/或受伤的损伤相关的分子模式已知组织会直接激活血小板，从而触发活性氧线粒体又导致血小板的凋亡和释放额外的mtDNA。这个提要 - 正向周期导致血小板激活和高凝性的升级，达到血栓形成遥控从mtDNA释放的最初位点。虽然PE患者的胎盘和母体mtDNA水平升高，但它是PE期间胎盘和全身循环中超凝性的调解人的作用调查。此外，循环mtDNA可以通过DNase I处理直接耗尽，已显示抑制体外和体内血小板激活和聚集。但是，dnase我从未被探讨过 PE的疗法。为了解决这个知识差距，我们建议检查mtDNA是否充当 PE期间胎盘和全身循环的高凝性，以及是否可以缓解这种影响通过DNase I使用RAT SFLT-1/SENG模型的严重PE处理。类似于严重的先兆前患者慢性SFLT-1和Seng输注对怀孕大鼠促进胎盘病理学，高血压，减少血小板计数和最终器官损伤。平行的离体研究将确定SFLT-1，Seng和胎盘mtDNA引起血小板激活，线粒体功能障碍和聚集。因此，通过申请综合性新方法，PE的临床相关模型以及高级方法论，我们将测试 MTDNA介导血小板激活，线粒体功能障碍，高凝性和严重PE中的血管功能障碍，并且通过DNase I治疗改善了该途径。发现这些开创性研究产生的可能会通过识别小说来彻底改变PE的护理标准靶向mtDNA的抗血栓形成剂具有潜在的对其他高凝状态的宽泛适用性。