Angiogenesis-related gene products in preeclampsia

描述(申请人提供)：先兆子痫(PE)是一种疾病，影响所有妊娠的5%-7%，特征是严重的高血压，蛋白尿和水肿。内皮功能障碍在本病的发病机制中起着重要作用，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会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患者的血清水平比正常血压的孕妇高。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。SFIT-1是FIT-1的一种分泌型剪接变异体(缺少跨膜区和细胞质结构域)，通过阻止它们与细胞表面受体的结合而有效地拮抗VEGF和PIGF。此外，我们还发现，与对照组相比，子痫前期孕妇分娩时血液中抗血管生成蛋白(SFIT-1)与促血管生成蛋白(VEGF+PIGF)的比率显著升高。在体外，先兆子痫患者血清而不是正常妊娠血清由于过量的sFIT-1而导致内皮功能障碍，而外源性的血管内皮生长因子和PIGF可以挽救这种功能。最后，我们有初步数据表明，外源性SFIT-1给孕鼠注射会导致高血压、大量蛋白尿和肾小球内皮细胞增生症，这是PE的经典病变。因此，我们假设由于sFlt-1过量导致的血管生成平衡的改变导致了PE的发生。本研究旨在阐明SFIT-1和血管生成平衡改变在PE发病机制中的作用。我们将首先描述我们的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SFIT-1和改变血管生成平衡导致全身血管功能障碍和胎盘细胞滋养细胞功能障碍的机制。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发病机制中的作用和探索治疗PE的新途径奠定基础。

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.