Mediators of impaired fetoplacental angiogenesis in fetal growth restriction

胎儿生长受限(FGR)是围产儿发病率和死亡率的第二大原因。严重者常合并胎盘血管阻力异常升高，临床表现为超声脐动脉多普勒指数异常。正是这些超声血流受损的胎儿，死产/死亡、神经发育迟缓和/或长期健康问题的风险最高。目前，除了分娩之外，没有其他预防或治疗措施，临床数据表明，这种干预仍然不会影响总体生存或长期结果。在这些严重的FGR病例中，一直可以看到的一个主要胎盘异常是胎盘内血管发育不足。这些胎盘具有异常细小和畸形的血管，这导致胎儿和胎盘内的血液流动不良，这在超声波上可以看到。我们实验室的长期目标是了解妊娠合并严重胎儿生长受限时发生的细胞和分子缺陷。目前，我们知道胎盘血管衬里的细胞--内皮细胞--存在导致它们异常迁移的分子异常，这是导致血管形成不足的主要原因之一。然而，很明显，在其他器官中，包围内皮细胞的非细胞、蛋白质组织--细胞外基质(ECM)--可以调节内皮细胞的属性，以促进和抑制血管形成。我们有强有力的初步数据表明，人胎盘中异常的EC-ECM相互作用导致EC增殖和迁移受损。因此，这项建议的主要目的是确定胎盘特异性EC-ECM相互作用在这些合并严重FGR的妊娠胎盘血管生长中的作用。为了实现这一目标，我们建议：[1]识别EC-to-ECM(Inside-Out)信号异常导致EC增殖和迁移受损，[2]识别ECM-to-EC(Outside-In)信号异常导致EC增殖和迁移受损，[3]确定严重FGR中ECs和ECM之间的双向信号异常调节的特定通路。完成所提出的目标不仅将确定EC和ECM在EC-ECM信号转导中的单独作用，而且还将确定在重度FGR胎盘中异常调控的血管生成的关键途径。这个实验模型将产生新的和临床相关的数据，为未来研究这些异常的分子和细胞事件是否可以被靶向和“拯救”奠定基础。虽然这种往往具有破坏性的并发症的胎儿治疗还不是迫在眉睫，但我们的实验将提供关于改善重度FGR孕妇胎儿-胎盘血流的潜在目标的关键见解。

Fetal growth restriction (FGR) is the second-leading cause of perinatal morbidity and mortality. Severe cases are oftentimes also complicated by abnormally high placental vascular resistance, as reflected clinically by abnormal umbilical artery Doppler indices on ultrasound. It is these fetuses with impaired blood flow on ultrasound that are at highest risk for stillbirth/death, neurodevelopmental delay, and/or long-term health problems. Currently, no preventative or therapeutic measures exist other than delivery, and clinical data show that this intervention still does not impact overall survival or long-term outcome. One major placental abnormality that is consistently seen in these severe cases of FGR is inadequate development of blood vessels within the placenta. These placentas have abnormally thin and malformed blood vessels, which leads to the poor blood flow within the fetus and placenta that can be seen on ultrasound. Our laboratory's long-term goal is to understand the cellular and molecular defects that occur in pregnancies complicated by severe fetal growth restriction. Currently, we know that cells lining the blood vessels of placentas - endothelial cells (ECs) - have molecular aberrations that cause them to migrate abnormally, which is one major cause of inadequate blood vessel formation. However, it is clear that in other organs, the non-cellular, proteinaceous tissue that surrounds ECs - the extracellular matrix (ECM) - can regulate EC cellular properties to promote and inhibit blood vessel formation. We have strong preliminary data showing that aberrant EC-ECM interactions in the human placenta result in impaired EC proliferation and migration. Thus, the main objective of this proposal is to determine the role of placental-specific EC-ECM interactions in the growth of placental blood vessels in these pregnancies complicated by severe FGR. To achieve this goal, we propose: [1] To identify abnormalities of EC-to-ECM (inside-out) signaling underlying impaired EC proliferation and migration, [2] To identify abnormalities of ECM-to-EC (outside-in) signaling underlying impaired EC proliferation and migration, and [3] To determine specific pathways regulated by faulty bi-directional signaling between ECs and ECM from severe FGR. Completion of the proposed aims will not only establish the individual roles of EC and ECM in EC-ECM signaling but will also identify key pathways of angiogenesis that are aberrantly regulated in placentas from severe FGR. This experimental model will generate new and clinically relevant data, setting a foundation for future studies investigating whether these abnormal molecular and cellular events can be targeted and "rescued." While fetal therapy for this often devastating complication is not on the immediate horizon, our experiments will provide key insights regarding potential targets for improving fetoplacental blood flow in pregnancies complicated by severe FGR.