Mechanisms of Vasoactive Mediator Action in FGR

描述（由申请人提供）：在发达国家，胎儿生长受限（FGR）使4%至7%的妊娠并发症，是围产期发病率和死亡率的主要原因。子宫胎盘灌注不足是FGR最常见的原因。胎盘灌注主要受局部作用的血管活性介质调节。本研究的目的是探讨两种血管活性介质参与FGR发病机制的机制。重点将放在内皮素-1（ET-1）和血小板活化因子（PAF）上，这两种都是有效的血管收缩剂。有证据表明，ET-1和PAF可能协同作用，减少灌注在病理条件下。ET-1和PAF在FGR的病理生理学中相互作用的机制将被研究。ET-1有助于调节子宫和胎盘血管张力。ET-1已被证明在三种不同FGR模型的病理生理学中发挥主要作用。除了其直接的血管收缩作用外，ET-1还上调PAF的产生，PAF是一种有效的血管活性和炎症介质。在这些模型中，内皮素受体A（ETA）拮抗剂改善胎盘灌注和胎儿生长。在初步的实验中，我们证明了胎盘灌注进一步提高了更高的选择性ETA拮抗剂。在一氧化氮合酶（NOS）抑制诱导的FGR中，将比较三种不同拮抗剂对胎盘灌注、胎儿生长和PAF表达的影响，这三种拮抗剂的ETA受体选择性程度不同。通过这种方式，将评估ETA调节PAF产生、子宫胎盘灌注和胎儿生长的程度。eNOS敲除（KO）小鼠也将用于评估在NO缺乏模型中子宫和胎盘中ET-1、ET受体和PAF的表达，而没有化学干预。这将允许进一步评估ETA和PAF拮抗作用对胎儿和胎盘生长以及血管活性介质表达的影响。为了研究这些介质的分子调节，将利用人类胎盘滋养层细胞，目的是了解调节胎盘中ET-1和PAF产生和作用的信号机制。这些研究将为这些重要的血管活性介质如何促进FGR的病理生理学提供新的见解。更好地了解这些机制可能有助于制定有意义的治疗干预措施，以改善FGR并发症的妊娠结局，特别是那些远离足月的妊娠。

DESCRIPTION (provided by applicant): Fetal growth restriction (FGR) complicates 4 to 7% of pregnancies in developed countries, and is a major contributor to perinatal morbidity and mortality. Inadequate uteroplacental perfusion is the most commonly recognized cause of FGR. Placental perfusion is largely regulated by locally acting vasoactive mediators. The purpose of the proposed research is to investigate the mechanisms by which two vasoactive mediators contribute to the pathogenesis of FGR. The focus will be on endothelin-1 (ET-1) and platelet activating factor (PAF), both potent vasoconstrictors. There is evidence to suggest that ET-1 and PAF may act synergistically to decrease perfusion under pathologic conditions. The mechanisms by which ET-1 and PAF interact in the pathophysiology of FGR will be investigated. ET-1 contributes to the regulation of uterine and placental vascular tone. ET-1 has been shown to play a primary role in the pathophysiology of three different models of FGR. Beyond its direct vasoconstrictive effects, ET-1 also upregulates the production of PAF, a potent vasoactive and inflammatory mediator. Endothelin receptor A (ETA) antagonism improves placental perfusion and fetal growth in these models. In preliminary experiments, we demonstrated that placental perfusion is further improved with a more highly selective ETA antagonist. In nitric oxide synthase (NOS) inhibition-induced FGR, the effect of three different antagonists, which vary with respect to their degree of ETA receptor selectivity, on placental perfusion, fetal growth, and PAF expression will be compared. In this way the degree to which ETA regulates PAF production, uteroplacental perfusion, and fetal growth will be evaluated. eNOS knockout (KO) mice will also be used to evaluate the expression of ET-1, ET receptors, and PAF in the uterus and placenta in a model of NO deficiency without chemical intervention. This will allow further evaluation of the effect of both ETA and PAF antagonism on fetal and placental growth and vasoactive mediator expression. To investigate the molecular regulation of these mediators, human placental trophoblasts will be utilized with a goal of understanding signaling mechanisms that regulate the production and action of both ET-1 and PAF in the placenta. These studies will provide new insights on how these prominent vasoactive mediators contribute to the pathophysiology of FGR. A better understanding of these mechanisms may allow for the development of meaningful therapeutic interventions to improve outcome in pregnancies complicated by FGR, particularly those remote from term.