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: 8708192
• 负责人: Rashmi Sood
• 金额: $ 36.75万
• 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/8708192
• 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)：血管通畅和充足的血液流动是正常胎盘功能的重要组成部分。引发胎盘血栓前改变的情况会影响血液流动，对母亲和婴儿都会产生严重的后果。后果包括胎儿生长受限、胎儿早期或晚期死亡以及母亲高血压疾病，如先兆子痫。这些疾病是由多因素引起的，影响了超过5%的妊娠。人类胎盘形成了一个不寻常的血管床，这是人体其他地方没有的。胎盘中的母体血管间隙由胎儿滋养层细胞排列，而不是母体血管内皮细胞。它是 尚不清楚这些血管空间的血液流动是如何维持的，以及是什么导致了病理性血栓形成。凝血和炎症之间的相互作用的动力学仍然不确定；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。我们已经建立了一种小鼠血栓形成-沉淀性胎盘衰竭和胎儿丢失的模型，该模型发生在没有血栓形成的情况下。我们发现，这一模型是由凝血酶介导的血小板激活驱动的，肝素治疗可以改善妊娠结局，但不能通过水飞蓟素、磺达肝素或直接的Xa抑制剂治疗。利用这一模型，我们检验了凝血酶介导的母体血小板激活通过不需要血栓形成或血小板聚集的机制导致胎盘衰竭的假设。我们检测了胎盘衰竭中血小板受体Ⅱb3、GPIb-V-IX和GPVI的作用，以及血小板释放反应，并确定胎盘衰竭是否与滋养层细胞的分化障碍或免疫细胞的募集有关。我们评估了上游外源性和内源性途径成分在疾病病理中的作用，基于血小板激活可以激活内源性途径成分或招募TF介导的炎症的基本原理。我们验证了这个模型中的胎盘衰竭是由滋养层细胞表面蛋白C激活中断引起的假设。在我们以前工作的基础上，我们测试了肝素的抗凝功能不是其有益效果所必需的假设。我们将我们的研究扩展到第二种胎盘衰竭模型，在这种模型中，雌激素磺基转移酶缺乏导致胎盘血栓形成，与母亲血小板对凝血酶的敏感性增加相关，并通过肝素治疗得到改善。拟议的研究调查了血小板重新聚集到胎盘的分子细节，以及血小板扰乱胎盘功能的机制。他们在体内胎盘发育和功能的背景下测试凝血生物学中当前范式的有效性。这些都是对胎儿-母体交界处的血小板和凝血活性的迫切需要的研究，对妊娠障碍具有直接意义。