Thursday, April 25, 2024
4/25/2024
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.
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