Mediators of impaired fetoplacental angiogenesis in fetal growth restriction

胎儿生长受限中胎儿胎盘血管生成受损的介质

• 批准号: 10247809
• 负责人: EMILY J SU
• 金额: $ 73.52万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247809
• 关键词: Abnormal Endothelial Cell; Actins; Adhesions; Angiogenesis Pathway; Atomic Force Microscopy; Binding; Biochemical Genetics; Biological Assay; Blood Vessels; Blood flow; Cell Communication; Cell Cycle; Cell Cycle Arrest; Cell Cycle Progression; Cell Proliferation; Cells; Cessation of life; Chorionic villi; Clinical; Clinical Data; Complex; Complication; Data; Defect; Development; Distal; Doppler velocimetry; Elements; Endothelial Cells; Event; Exhibits; Experimental Models; Extracellular Matrix; Extracellular Matrix Proteins; Fetal Growth Retardation; Fetus; Fibroblasts; Fibronectins; Focal Adhesions; Foundations; Future; Gestational Age; Goals; Growth; Health; Human; Image; Impairment; Individual; Integrin Binding; Integrin alpha5beta1; Integrin alphaVbeta3; Integrins; Intervention; Knowledge; Laboratories; Ligand Binding; Ligands; Mass Spectrum Analysis; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Abnormality; Organ; Outcome; Pathway interactions; Perinatal; Perinatal mortality demographics; Placenta; Pregnancy; Property; Proteins; Protocols documentation; Public Health; Recycling; Regulation; Research; Research Project Grants; Risk; Role; Signal Pathway; Signal Transduction; Structure of thyroid parafollicular cell; Structure of umbilical artery; Surface; Talin; Testing; Therapeutic; Thinness; Tissues; Ultrasonography; Vascular resistance; Villous; angiogenesis; base; blood vessel development; cell motility; clinically relevant; experimental study; fetal; fluorophore; genetic manipulation; hemodynamics; high risk; improved; indexing; insight; live cell imaging; migration; novel; perinatal morbidity; phosphoproteomics; prenatal therapy; preservation; receptor; stillbirth; therapy development; trafficking; transcriptome sequencing

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.

胎儿生长受限（FGR）是围产期发病率和死亡率的第二大原因。严重的病例通常还伴有异常高的胎盘血管阻力，如超声上异常的脐动脉多普勒指数所反映的临床。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，除了分娩外，没有其他预防或治疗措施，临床数据显示这种干预仍然不影响总生存率或长期结局。在这些严重的FGR病例中经常看到的一个主要胎盘异常是胎盘内血管发育不足。这些胎盘有异常薄和畸形的血管，这导致胎儿和胎盘内的血流不畅，可以在超声上看到。我们实验室的长期目标是了解严重胎儿生长受限的妊娠中发生的细胞和分子缺陷。目前，我们知道胎盘血管的内皮细胞（EC）具有分子畸变，导致它们异常迁移，这是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EC的非细胞蛋白质组织-细胞外基质（ECM）-可以调节EC细胞特性以促进和抑制血管形成。我们有强有力的初步数据表明，异常的EC-ECM相互作用在人胎盘的EC增殖和迁移受损的结果。因此，该建议的主要目的是确定胎盘特异性EC-ECM相互作用在这些妊娠并发严重FGR的胎盘血管生长中的作用。为了实现这一目标，我们提出：[1]鉴定EC增殖和迁移受损的EC到ECM（由内向外）信号传导的异常，[2]鉴定EC增殖和迁移受损的EC到EC（由外向内）信号传导的异常，以及[3]确定由严重FGR的EC和ECM之间的错误双向信号传导调节的特定途径。所提出的目标的完成不仅将建立EC和ECM在EC-ECM信号传导中的个体作用，而且还将确定在重度FGR的胎盘中异常调节的血管生成的关键途径。该实验模型将产生新的临床相关数据，为未来研究这些异常分子和细胞事件是否可以被靶向和“拯救”奠定基础。“虽然这种通常具有破坏性的并发症的胎儿治疗并没有立即出现，但我们的实验将为改善严重FGR并发症的妊娠中胎儿胎盘血流的潜在靶点提供关键见解。