Role of Maternal Platelets in the Placenta and Pregnancy Complications

母体血小板在胎盘和妊娠并发症中的作用

• 批准号: 8578439
• 负责人: Rashmi Sood
• 金额: $ 35.7万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578439
• 关键词: Accounting; Adhesions; Affect; Animals; Antibodies; Anticoagulation; Antisense Oligonucleotides; Biology; Blocking Antibodies; Blood Platelets; Blood Vessels; Blood flow; Breeding; Cardiovascular system; Cell surface; Cells; Coagulation Process; Complex; Data; Disease; Estrone sulfotransferase; Event; Failure; Fetal Death; Fetal Growth Retardation; Generations; Genetic; Glycoproteins; Heparin; Hirudin; Hirudins; Human; Immune; Immunologic Surveillance; Individual; Inflammation; Integrins; Investigation; Knock-out; Life; Mediating; Modeling; Molecular; Morbidity - disease rate; Mothers; Mus; Mutate; Mutation; Outcome; Pathology; Pathway interactions; Placenta; Placental Circulation; Placentation; Platelet Activation; Platelet Transfusion; Platelet aggregation; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Process; Protein C; Prothrombin; Reaction; Recruitment Activity; Rodent; Role; Testing; Thrombin; Thrombin Receptor; Thrombomodulin; Thrombophilia; Thrombosis; Transgenic Organisms; Vascular Endothelium; Vascular Patency; Work; activated Protein C; base; fetal; fondaparinux; improved; in vivo; inhibitor/antagonist; mortality; pregnancy disorder; public health relevance; receptor; research study; trophoblast; vascular bed

DESCRIPTION (provided by applicant): Vascular patency and adequate blood flow are essential components of normal placental function. Conditions that trigger prothrombotic changes in the placenta compromise blood flow and have serious consequences for both the mother and the baby. Consequences include fetal growth restriction, early or late fetal death and maternal hypertensive disorders, such as preeclampsia. These are disorders of multifactorial origin that affect more than 5% of all pregnancies. The human placenta forms an unusual vascular bed not found anywhere else in the body. The maternal vascular spaces in the placenta are lined by fetal trophoblast cells, rather than the maternal vascular endothelium. It is unclear how blood flow is maintained in these vascular spaces and what leads to pathological thrombosis. The dynamics of interplay between coagulation and inflammation remain undefined; these are likely to of significance since the placenta must evade immune surveillance in order to thrive. We have developed a murine model of thrombophilia-precipitated placental failure and fetal loss that occurs in the absence of thrombosis. We find that this model is driven by thrombin-mediated platelet activation and that pregnancy outcome is improved by heparin treatment, but not by treatment with hirudin, fondaparinux or a direct Xa inhibitor. Using this model we test the hypothesis that thrombin-mediated activation of maternal platelets causes placental failure through mechanisms that do not require thrombosis or platelet aggregation. We examine the contributions of platelet receptors ¿II¿b3, GPIB-V-IX and GPVI, and platelet release reaction to placental failure, and determine if placental failure is associated with impaired differentiation of trophoblast cells or the recruitment of immune cells. We evaluate the contributions of upstream extrinsic and intrinsic pathway components to disease pathology, based on the rationale that platelet activation can invoke the activation of intrinsic pathway components or recruit TF-mediated inflammation. We test the hypothesis that placental failure in this model is caused by the disruption of protein C activation on trophoblast cell surface. Building on our previous work, we test the hypothesis that the anticoagulation function of heparin is not required for its beneficial effect. We expand our studies to a second model of placental failure in which a deficiency of estrogen sulfotransferase causes placental thrombosis associated with increased sensitivity of maternal platelets to thrombin and is improved by heparin treatment. Proposed studies investigate the molecular details of platelet recruitment to the placenta and the mechanisms by which by which platelets disrupt placental function. They test the validity of current paradigms in coagulation biology in the in vivo context of placental development and function. These are much-needed investigations into platelet and coagulation activities at the feto-maternal interface with direct significance for pregnancy disorders.

描述（由申请人提供）：血管通畅性和充足的血流是正常胎盘功能的基本组成部分。触发胎盘血栓前变化的条件会损害血流，对母亲和婴儿都有严重后果。其后果包括胎儿生长受限，早期或晚期胎儿死亡和母体高血压疾病，如先兆子痫。这些是多因素起源的疾病，影响所有怀孕的5%以上。人类胎盘形成了一个不寻常的血管床，在身体的其他任何地方都没有发现。胎盘中的母体血管空间由胎儿滋养层细胞排列，而不是母体血管内皮。是 尚不清楚这些血管间隙中的血流是如何维持的，以及是什么导致病理性血栓形成。凝血和炎症之间相互作用的动力学尚不明确;这些可能具有重要意义，因为胎盘必须逃避免疫监视才能茁壮成长。我们已经建立了一个小鼠血栓形成倾向性胎盘衰竭和胎儿丢失的模型，发生在没有血栓形成。我们发现，这种模式是由凝血酶介导的血小板活化和妊娠结局改善肝素治疗，但不是水蛭素，磺达肝癸钠或直接Xa抑制剂治疗。使用这个模型，我们测试的假设，凝血酶介导的激活母体血小板导致胎盘衰竭的机制，不需要血栓形成或血小板聚集。我们研究了血小板受体<$II <$b3、GPIB-V-IX和GPVI的作用，以及血小板释放对胎盘衰竭的反应，并确定胎盘衰竭是否与滋养层细胞分化受损或免疫细胞的募集有关。我们评估了上游外在和内在途径成分对疾病病理学的贡献，其依据是血小板活化可以激活内在途径成分或招募TF介导的炎症。我们测试的假设，在这个模型中，胎盘衰竭是由破坏蛋白C激活滋养层细胞表面。在我们以前工作的基础上，我们检验了肝素的抗凝功能不是其有益作用所必需的假设。我们将研究扩展到第二种胎盘衰竭模型，其中雌激素磺基转移酶缺乏导致胎盘血栓形成，并伴有母体血小板对凝血酶的敏感性增加，肝素治疗可改善这种情况。拟议的研究调查血小板募集到胎盘的分子细节和血小板破坏胎盘功能的机制。他们在胎盘发育和功能的体内背景下测试凝血生物学的当前范例的有效性。这些是非常需要的调查血小板和凝血活动在胎儿-母亲界面与妊娠疾病的直接意义。