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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

基本信息

批准号：
10661047
负责人：
EMILY J SU
金额：
$ 73.14万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661047
关键词：
Actins Adhesions Angiogenesis Pathway Atomic Force Microscopy Binding Biochemical Biological Assay Blood Vessels Blood flow Cell Communication Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Line Cell Proliferation Cells Cessation of life Chorionic villi Clinical Clinical Data Complex Complication Cytoskeleton 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 Modeling Molecular Molecular Abnormality Organ Outcome Pathway interactions Perinatal Perinatal mortality demographics Placenta Pregnancy Pregnancy Complications Proliferating 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 Vascular resistance Villous Western Blotting angiogenesis blood vessel development cell motility clinically relevant comparison control experimental study fetal fluorophore genetic manipulation hemodynamics high risk improved indexing insight live cell imaging malformation migration novel perinatal morbidity phosphoproteomics prenatal therapy preservation receptor stillbirth therapy development trafficking transcriptome sequencing ultrasound

项目摘要

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。严重者还常伴有胎盘血管阻力异常高，临床表现为超声脐动脉多普勒指数异常。正是这些超声显示血流受损的胎儿，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，没有预防或治疗措施存在，临床数据表明，这种干预仍然不影响总生存或长期结局。在这些严重的FGR病例中，一个主要的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液流动不畅，这可以在超声波上看到。我们实验室的长期目标是了解在严重胎儿生长受限的妊娠中发生的细胞和分子缺陷。目前，我们知道胎盘血管内壁的细胞内皮细胞（ECs）存在分子畸变，导致它们异常迁移，这是血管形成不足的一个主要原因。然而，在其他器官中，内皮细胞周围的非细胞蛋白组织-细胞外基质(ECM) -可以调节内皮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，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，本研究的主要目的是确定胎盘特异性EC-ECM相互作用在合并严重FGR的妊娠中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- To -ECM（内向外）信号异常导致EC增殖和迁移受损；[2]鉴定ECM- To -EC（外向内）信号异常导致EC增殖和迁移受损；[3]鉴定严重FGR中EC和ECM之间双向信号异常调控的特定通路。完成所提出的目标不仅将确定EC和ECM在EC-ECM信号传导中的个体作用，还将确定严重FGR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靶向和“拯救”奠定基础。虽然这种毁灭性并发症的胎儿治疗还没有出现，但我们的实验将为改善严重FGR妊娠中胎儿胎盘血流的潜在靶点提供关键见解。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Angiogenic Function of Human Placental Endothelial Cells in Severe Fetal Growth Restriction Is Not Rescued by Individual Extracellular Matrix Proteins.

DOI：
10.3390/cells12192339
发表时间：
2023-09-23
期刊：
Cells
影响因子：
6
作者：
通讯作者：

Term Human Placental Trophoblasts Express SARS-CoV-2 Entry Factors ACE2, TMPRSS2, and Furin.

术语人胎盘滋养细胞表达SARS-COV-2进入因子ACE2，TMPRSS2和FURIN。

DOI：
10.1128/msphere.00250-21
发表时间：
2021-04-14
期刊：
mSphere
影响因子：
4.8
作者：
Ouyang Y;Bagalkot T;Fitzgerald W;Sadovsky E;Chu T;Martínez-Marchal A;Brieño-Enríquez M;Su EJ;Margolis L;Sorkin A;Sadovsky Y
通讯作者：
Sadovsky Y

Human placental villous stromal extracellular matrix regulates fetoplacental angiogenesis in severe fetal growth restriction.

DOI：
10.1042/cs20201533
发表时间：
2021-05-14
期刊：
Clinical science (London, England : 1979)
影响因子：
0
作者：
Ji S;Gumina D;McPeak K;Moldovan R;Post MD;Su EJ
通讯作者：
Su EJ

Impaired fetoplacental angiogenesis in growth-restricted fetuses with abnormal umbilical artery doppler velocimetry is mediated by aryl hydrocarbon receptor nuclear translocator (ARNT).

脐动脉多普勒测速异常的生长受限胎儿的胎儿胎盘血管生成受损是由芳基烃受体核转位器（ARNT）介导的。

DOI：
10.1210/jc.2014-2385
发表时间：
2015
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
0
作者：
Su,EmilyJ;Xin,Hong;Yin,Ping;Dyson,Matthew;Coon,John;Farrow,KathrynN;Mestan,KarenK;Ernst,LindaM
通讯作者：
Ernst,LindaM

Dichotomous effects of aryl hydrocarbon receptor (AHR) activation on human fetoplacental endothelial cell function.