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: 7010387
• 负责人: S. Ananth Karumanchi
• 金额: $ 33.2万
• 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/7010387
• 关键词: angiogenesis; cell differentiation; chemical structure function; clinical research; disease /disorder model; drug screening /evaluation; female; genetically modified animals; growth factor; growth factor receptors; human pregnant subject; immunocytochemistry; laboratory mouse; laboratory rat; morphometry; pathologic process; patient oriented research; placenta; posttranscriptional RNA processing; preeclampsia; protein metabolism; tissue /cell culture; trophoblast; vascular endothelial growth factors; women' s health

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）：子痫前期（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。内皮功能障碍在这种疾病的发病机制中起重要作用；然而，病因和机制尚不清楚。我们最近发现，子痫前期患者的胎盘产生过量的天然抗血管生成蛋白，sft -1（可溶性纤维样酪氨酸激酶-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（PIGF）的酪氨酸激酶受体之一。fit1是fit1的一种分泌剪接变体（缺乏跨膜和细胞质结构域），通过阻止VEGF和PIGF与细胞表面受体的结合，可以有效地拮抗VEGF和PIGF。此外，我们发现，与对照组孕妇相比，子痫前期妇女分娩时母体血液中抗血管生成（sft -1）与促血管生成（VEGF + PIGF）蛋白的比例显著升高。在体外实验中，子痫前期血清而非正常妊娠血清由于过量的sfit1而诱导内皮功能障碍，可通过外源性VEGF和PIGF来挽救。最后，我们有初步的数据表明，给妊娠大鼠注射外源性sFIt-1会导致高血压、蛋白尿和肾小球内皮增生，这是典型的PE病变。因此，我们假设过量的sFLt-1导致血管生成平衡的改变导致PE的发生。本研究旨在阐明sfit1和血管生成平衡改变在PE发病机制中的作用。我们将首先表征我们的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，我们将通过体外和体内实验阐明过量的sfit1和改变的血管生成平衡诱导的全身血管功能障碍和胎盘细胞滋养层功能障碍的机制。最后，我们将重点研究胎盘细胞滋养细胞产生sFIt-1的转录和转录后调控机制。这些重点研究将为理解血管生成相关基因产物在PE发病机制中的作用以及探索PE治疗的新途径奠定基础。