The use of a biopolymer-fused form of VEGF-B for the treatment of Preeclampsia.

项目摘要/摘要。 先兆子痫的临床特征是血压升高并伴有 妊娠中期和晚期出现蛋白尿或其他症状。在分子水平上，它有 已有研究表明，在治疗过程中，一些抗血管生成因子，如可溶性Flt-1(sFlt-1)增加。 在这些妇女中怀孕。这些因素的存在被认为与系统内皮细胞有关。 功能障碍，导致血压升高和产妇综合症的其他症状。 血管内皮生长因子(VEGF)家族蛋白负责血管生成和 内皮细胞通过与包括Flt-1和Flk-1在内的一组受体相互作用而发挥功能。可溶性的sFlt-1 Flt-1受体胞外区的形式在先兆子痫妇女的血液中上调，并且 起到血管内皮生长因子陷阱的作用，阻止健康的血管内皮生长因子信号传递给内皮细胞，促进内皮细胞的生长 功能障碍。因此，中和循环中增加的sflt-1的治疗策略是治疗 先兆子痫治疗。我的PI实验室之前的研究表明，血管内皮生长因子-A的给药与 胎盘缺血大鼠模型中弹性蛋白样多肽(ELP)载体蛋白的表达显著降低 自由S-Flt1水平和正常血压。ELP-VEGF-A蛋白可结合并激活Flk-1 也可通过隔离循环中的S-Flt-1发挥作用，从而释放内源性血管内皮生长因子-A。 结合Flk-1受体，改善内皮功能。然而，血管内皮生长因子-A政府有许多 不良反应是通过激活Flk-1受体介导的。因此，新的治疗策略 我们实验室使用的是利用其他形式的血管内皮生长因子，包括血管内皮生长因子-B，它与sflt-1结合，但不 直接激活的Flk-1。本研究的目的是确定丹参的药理作用和疗效。 ELP-VEGF-B治疗子痫前期我们将使用已建立的胎盘缺血模型 作为降低子宫灌流压(RUPP)的模型，它与许多表型非常相似 先兆子痫的特点。我们将检验这样一种假设，即使用生物聚合物融合形式的血管内皮生长因子治疗- B将隔离sFlt-1和游离内源性VEGF-A，这将导致内皮功能的改善 并在胎盘缺血模型中降低血压。在目标1中，我们将测定其体外活性 ELP-VEGF-B的体内药代动力学、生物分布、胎盘转运和毒性 静脉和皮下给药。在目标2中，我们将确定ELP-VEGF的治疗效果。 B用于治疗先兆子痫的母体综合征。先兆子痫临床特征的改善 可能被证明延长了发育中胎儿的妊娠期，也减轻了疾病对 母亲。我们认为，通过探索不同疗法的使用来治疗先兆子痫 综合征，我们可以减少与疾病相关的后遗症，并改善孕妇和 他们的孩子。

Project Summary/Abstract. Preeclampsia is clinically characterized by the development of elevated blood pressure combined with proteinuria or other symptoms during the second and third trimester of pregnancy. On the molecular level, it has been shown that there is an increase in a number of anti-angiogenic factors, such as soluble Flt-1 (sFlt-1), during pregnancy in these women. The presence of these factors is believed to be involved in the systemic endothelial dysfunction which contributes to the elevation in blood pressure and other symptoms of the maternal syndrome. The Vascular Endothelial Growth Factor (VEGF) family of proteins are responsible for angiogenesis and endothelial cell function via their interaction with a group of receptors including Flt-1 and Flk-1. sFlt-1, a soluble form of the extracellular domain of the Flt-1 receptor, is upregulated in the blood of preeclamptic women and functions as a VEGF trap, preventing healthy VEGF signaling to endothelial cells and contributing to endothelial dysfunction. Thus, therapeutic strategies to neutralize the increased circulating sFlt-1 are leading candidates for preeclampsia therapy. Previous studies in my PI’s lab have shown that administration of VEGF-A bound to a carrier protein called Elastin-like polypeptide (ELP) in a rodent model of placental ischemia significantly reduced free s-Flt1 levels and normalized blood pressure. The ELP-VEGF-A protein can bind and activate the Flk-1 receptor directly, and it can also function by sequestering circulating s-Flt-1, which frees endogenous VEGF-A to bind the Flk-1 receptor and improve endothelial function. However, VEGF-A administration has a host of adverse side effects mediated through its activation of the Flk-1 receptor. Therefore, the new therapeutic strategy being employed by our lab is to utilize other isoforms of VEGF, including VEGF-B, that bind to sFlt-1 but do not directly active Flk-1. The objective of this study is to determine the pharmacological properties and efficacy of ELP-VEGF-B for the treatment of preeclampsia. We will use an established model of placental ischemia known as the reduced uterine perfusion pressure (RUPP) model, which closely resembles many of the phenotypical features of preeclampsia. We will test the hypothesis that treatment with a biopolymer-fused form of VEGF- B will sequester sFlt-1 and free endogenous VEGF-A, which will result in improved endothelial function and reduced blood pressure in a model of placental ischemia. In Aim 1, we will determine the in vitro activity and in vivo pharmacokinetics, biodistribution, placental transfer, and toxicity profile of ELP-VEGF-B following intravenous and subcutaneous administration. In Aim 2, we will determine the therapeutic efficacy of ELP-VEGF- B for treatment of the maternal syndrome of preeclampsia. Improvements in the clinical features of preeclampsia may prove to increase the gestational period of developing fetuses and also lessen the burden of disease on the mother. We believe that by exploring the use of different therapeutics for the treatment of the preeclamptic syndrome, we can reduce the sequalae associated the disease and improve outcomes for pregnant women and their children.