Endogenous Apelin Receptor Ligands and Early Stages of Preeclamptic Pregnancy

子痫前期(PE)是一种威胁生命的高血压性妊娠障碍，发生在所有妊娠的5%-7% 案子。尽管有许多关于PE的研究，但对于这种疾病还没有具体的治疗选择。 了解导致PE的分子因素可以为可能的治疗干预提供基础 降低这种疾病的发病率，提高母婴存活率，最终导致改善 人群的心血管健康。孕期胎儿-母体界面的调节机制 导致PE的定义不是很好。Apeline能系统，由Apelin、Elabela(Ela)和Apelin组成 受体(APJ)是一种新的多效性通路，具有潜在的治疗靶向。关键初步报告 数据显示阿佩林可降低血压、蛋白尿和改善子宫胎盘血流动力学。 在PE大鼠模型中。APELIN和ELA都作用于APELIN受体，并能刺激滋养层功能，然而， Apelin或Elas作用于滋养层细胞侵袭的分子机制及其治疗潜力 PE中的这两种多肽都是未知的。根据我们已公布的初步数据，我们假设阿佩林和 ELABELA通过刺激滋养层细胞侵袭促进胎盘形成，该作用涉及到 丝裂原活化蛋白激酶/细胞外信号调节激酶和mircoRNA199信号通路。 我们进一步假设宫内局部给药APELIN或ELABELA可改善滋养层细胞 侵袭子宫胎盘血流动力学，降低PE的发展特点。通过使用 分子、基因组、生化、细胞和生理技术的多学科方法，我们将 建立APELIN和ELA的主要形式的生化性质和药理性质 APJ在胎盘和滋养层细胞中的表达(目标1)；建立apeline能系统在PE中的治疗潜力 (目标2)；并确定apelin和Ela导致滋养层细胞增加的分子基础 正常大鼠、子痫前期大鼠胎盘和人胎盘滋养层细胞原代培养的侵袭性 滋养层细胞系(目标3)。我们的研究将确立apeline能系统作为一种新的 调节早孕的分子途径促进了我们对内源性调节的认识 胎儿-母体接口和建立apeline能系统作为PE治疗的新途径。

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.