Angiogenesis-related gene products in preeclampsia

先兆子痫中血管生成相关的基因产物

• 批准号: 7365256
• 负责人: S. Ananth Karumanchi
• 金额: $ 20.54万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7365256
• 关键词: Affect; Angiogenic Factor; Angiogenic Proteins; Animal Model; Binding; Biological Assay; Blood Circulation; Blood Coagulation Disorders; Blood Vessels; Cell Surface Receptors; Clinical; Cytoplasmic Tail; Data; Development; Disease; Edema; Equilibrium; Etiology; Event; Functional disorder; Gene Expression; Gene Expression Regulation; Heterozygote; Hypertension; Hypoxia; Immunohistochemistry; In Vitro; Ischemia; Kidney Failure; Knockout Mice; Lead; Lesion; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Pathogenesis; Patient currently pregnant; Patients; Placenta; Placental Growth Factor; Placentation; Play; Pre-Eclampsia; Pregnancy; Pregnant Women; Prevention; Production; Properdin; Proteins; Proteinuria; RNA Splicing; Rattus; Receptor Protein-Tyrosine Kinases; Reporting; Research Personnel; Rodent; Role; Serum; Symptoms; Testing; Therapeutic; Time; Transcriptional Activation; Up-Regulation; Variant; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Week; Woman; angiogenesis; antiangiogenesis therapy; cytotrophoblast; falls; fetal; glomerular filtration; in vivo; in vivo Bioassay; insight; mortality; normotensive; novel; novel therapeutics; podocyte; prevent; programs; research study; response

DESCRIPTION (provided by applicant): Preeclampsia (PE) is a disease, which affects 5-7% of all pregnancies and is characterized by severe hypertension, proteinuria and edema. Endothelial dysfunction plays an important role in the pathogenesis of this disorder; however, the etiology and mechanisms are still unknown. We recently found that placentas from preeclamptic patients produce an excess of a naturally occurring anti-angiogenic protein, sFIt-1 (soluble fms-like tyrosine kinase-1), resulting in increased serum levels in patients with PE as compared to normotensive pregnant women. Fit-1 is one of the tyrosine kinase receptors for vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). sFIt-1, a secreted splice variant of Fit-1 (lacking the transmembrane and cytoplasmic domains) potently antagonizes VEGF and PIGF, by preventing their binding to the cell-surface receptor. Moreover, we have found that the ratio of anti-angiogenic (sFIt-1) to pro-angiogenic (VEGF + PIGF) proteins in the maternal bloodstream at the time of delivery is substantially elevated in preeclamptic women as compared with control pregnant women. In vitro, preeclamptic serum but not normal pregnant serum induces endothelial dysfunction due to excess sFIt-1, which can be rescued by exogenous VEGF and PIGF. Finally, we have preliminary data that administration of exogenous sFIt-1 to pregnant rats induces hypertension, heavy proteinuria and glomerular endotheliosis, the classic lesion of PE. We therefore hypothesize that alteration in the angiogenic balance due to excess sFLt-1 results in the development of PE. This proposal aims to clarify the role of sFIt-1 and altered angiogenic balance in the pathogenesis of PE. We will first characterize our sFIt-1 induced animal model for PE and will test several therapeutic compounds in an attempt to find new treatment options for patients with PE. We will then elucidate the mechanisms of systemic vascular dysfunction and placental cytotrophoblast dysfunction induced by excess sFIt-1 and altered angiogenic balance using both in vitro and in vivo experiments. Finally, we will focus on studying the transcriptional and post-transcriptional regulatory mechanisms of sFIt-1 production by placental cytotrophoblasts. These focused studies will form the beginnings of a framework for understanding the role of angiogenesis-related gene products in pathogenesis of PE and for exploring novel avenues for the treatment of PE.

描述（由申请人提供）：先兆子痫（PE）是一种疾病，影响所有妊娠的5-7%，其特征是严重的高血压、蛋白尿和水肿。内皮功能障碍在该病的发病机制中起重要作用，但其病因和机制尚不清楚。我们最近发现先兆子痫患者的胎盘产生过量的天然抗血管生成蛋白sFIt-1（可溶性fms样酪氨酸激酶-1），导致PE患者的血清水平高于血压正常的孕妇。Fit-1是血管内皮生长因子（VEGF）和胎盘生长因子（PlGF）的酪氨酸激酶受体之一。sFIt-1是Fit-1的分泌剪接变体（缺乏跨膜和胞质结构域），通过阻止VEGF和PlGF与细胞表面受体结合而有效拮抗VEGF和PlGF。此外，我们发现，与对照孕妇相比，先兆子痫孕妇分娩时母体血流中抗血管生成蛋白（sFIt-1）与促血管生成蛋白（VEGF + PlGF）的比例大幅升高。在体外，先兆子痫血清而不是正常妊娠血清诱导内皮功能障碍，由于过量的sFIt-1，这可以通过外源性VEGF和PIGF拯救。最后，我们有初步的数据表明，外源性sFIT-1给药妊娠大鼠诱导高血压，重蛋白尿和肾小球内皮增生，PE的经典病变。因此，我们推测，由于过量sFLt-1导致的血管生成平衡的改变导致PE的发展。该提案旨在阐明sFIt-1和血管生成平衡改变在PE发病机制中的作用。我们将首先表征sFIt-1诱导的PE动物模型，并将测试几种治疗化合物，试图为PE患者找到新的治疗选择。然后，我们将阐明全身血管功能障碍和胎盘细胞滋养层功能障碍诱导过量的sFIT-1和改变血管生成的平衡，在体外和体内实验的机制。最后，我们将重点研究胎盘细胞滋养层细胞产生sFIt-1的转录和转录后调节机制。这些重点研究将形成一个框架的开始，了解血管生成相关的基因产物在PE发病机制中的作用，并探索治疗PE的新途径。