Endogenous Apelin Receptor Ligands and Early Stages of Preeclamptic Pregnancy

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Preeclampsia (PE) is a life threatening hypertensive pregnancy disorder that occurs in 5-7% of all pregnancy cases. Despite numerous studies on PE, there are no specific treatment options available for this disorder. Understanding molecular factors that lead to PE could provide a basis for therapeutic interventions that may reduce the incidence of this disease, improve maternal and fetal survival, ultimately leading to improved cardiovascular health of the population. The mechanisms regulating feto-maternal interface during pregnancy leading to PE are not well defined. The apelinergic system, consisting of apelin, elabela (ELA), and the apelin receptor (APJ), is a novel pleiotropic pathway with a potential for therapeutic targeting in PE. Critical preliminary data demonstrate that apelin reduces blood pressure, proteinuria, and improves uteroplacental hemodynamics in PE rat model. Both, apelin and ELA act on apelin receptor and can stimulate trophoblast function, however, the molecular mechanisms of apelin or ELAs actions on trophoblast invasion and the therapeutic potential of either peptide in PE are unknown. Based on our published and preliminary data we hypothesize that apelin and elabela facilitate placentation via stimulatory actions on trophoblast invasion that involve the regulation of mitogen-activated protein kinase/ extracellular signal-regulated kinase and mircoRNA199 signaling pathways. We further hypothesize that the local intrauterine administration of apelin or elabela improves trophoblast invasion and uteroplacental hemodynamics, and reduce the development of PE features. By using multidisciplinary approach with molecular, genomic, biochemical, cellular, and physiological techniques, we will establish the biochemical properties of the major forms of apelin and ELA, and pharmacological properties of APJ in the placenta and trophoblast cells (Aim 1); establish the therapeutic potential of apelinergic system in PE (Aim 2); and determine molecular underpinnings of apelin and ELA actions leading to increased trophoblast cell invasion in primary cultures of trophoblast cells isolated from normal and preeclamptic rat placentas and human trophoblast cell lines (Aim 3). Our studies will establish the significance of the apelinergic system as a novel molecular pathway regulating early pregnancy advancing our knowledge on the endogenous regulation of the feto-maternal interface and establishing the apelinergic system as a novel therapeutic pathway in PE.