Role of natriuretic peptides in the ductus arteriosus

说明(申请人提供)：利钠肽(NPs)通过利尿、利钠和血管活性调节血压和液体平衡，是成人和儿童心力衰竭的生物标志物。由于心脏负荷过重，动脉导管未闭(PDA)婴儿的ANP和BNP水平升高。血浆NP水平在PDA治疗后很快恢复正常。这些发现表明，NPs主要反映心脏状态，但我们推测，在PDA存在的情况下，NPs的持续升高可能会增强DA的松弛，并创建一种前馈机制，进一步抑制DA的关闭。我们观察到NPs导致DA扩张，这进一步促使我们推测，NP给药可能是维持出生后DA通畅的一种新方法。关于NPs在DA发育中的作用或作为DA语调的中介的信息很少。我们的初步数据显示，Npr1、Npr2和Npr3受体在胎儿和新生小鼠DA中有不同的表达。分离的胎鼠DA暴露在不同的NPs中，在胎儿和新生儿的氧气条件下，对CNP&GT；ANP&GT；BNP产生剂量依赖性的扩张。此外，患有PDA的小鼠循环NP水平升高。我们假设：1)NPs介导DA的松弛，并可能延长出生后DA的开放时间；2)PDA和继发性充血性心力衰竭引起的出生后NP水平升高有助于维持DA处于非收缩状态。这一假设将从三个具体目标进行检验。目的1在PDA小鼠模型和培养的DA细胞中，确定NPs及其受体在胎儿和新生DA中的表达模式。目的2体外研究NP对野生型(早产期与足月期)小鼠、用NP拮抗剂治疗的野生型小鼠、Npr1(-/-)和Npr2(-/-)小鼠、具有PDA表型的小鼠(COX-1(-/-)/COX-2(-/-)和COX抑制小鼠)以及出生后P1和P2小鼠的闭合性DA的影响。CGMP的产生和受体的亲和力将被确定。目的3将在体内确定：足月新生儿对NPs暴露的反应(防止出生后闭合)；对胎儿暴露于NP受体拮抗剂的反应(诱导胎儿DA收缩)；以及NP拮抗剂对小鼠PDA模型的影响(诱导新生儿PDA收缩)。这些研究将为NPs作为DA介体的新角色提供新的信息，并确定新的潜在的DA调节治疗靶点。 公共卫生相关性：动脉导管是一种胎儿血管，由于其在将含氧血液从胎盘输送到胎儿器官和组织中的作用，其通畅性对子宫内的存活至关重要。胎儿中这条血管的异常收缩或新生儿不能正确关闭是有害的，特别是在早产儿中，但调节这条血管的机制尚不清楚。这项提议将检验以下假设：利钠肽是对液体平衡和血压控制至关重要的信号分子，在正常动脉导管的调节中发挥重要作用，并导致动脉导管在出生后未能收缩的病理状态。

DESCRIPTION (provided by applicant): Natriuretic peptides (NPs) regulate blood pressure and fluid balance via their diuretic, natriuretic, and vasoactive properties, and are biomarkers of heart failure in adults and children. Infants with patent ductus arteriosus (PDA) have increased ANP and BNP levels due to cardiac overload. NP levels normalize soon after PDA treatment. These findings suggest that NPs primarily reflect cardiac status, but we speculate that ongoing elevation of NPs in the presence of PDA could augment DA relaxation and create a feed-forward mechanism to further inhibit DA closure. Our observation that NPs induce DA dilation prompts further speculation that NP administration may be a novel approach to maintain patency of the postnatal DA. Little information exists on the role of NPs in DA development or as mediators of DA tone. Our preliminary data show that the Npr1, Npr2, and Npr3 receptors are differentially expressed in the fetal and newborn mouse DA. Exposure of the isolated fetal mouse DA to different NPs produced dose-dependent dilation to CNP>ANP>BNP under fetal and newborn oxygen conditions. Moreover, mice with PDA have elevated circulating NP levels. We hypothesize that: 1) NPs mediate relaxation of the DA and may prolong patency of the postnatal DA, and 2) elevated postnatal NP levels due to PDA and secondary congestive heart failure help to maintain the DA in a non-contractile state. This hypothesis will be examined in three specific aims. Aim 1 will determine the expression pattern of NPs and their receptors in the fetal and newborn DA, in mouse models of PDA, and cultured DA cells. Aim 2 will determine, in vitro, NP-induced changes in the tone of DAs from: wild type (preterm vs. term) mice, wild type mice treated with NP antagonists, Npr1 (-/-) and Npr2 (-/-) mice, mice with a PDA phenotype (COX-1(-/-) /COX-2(-/-) and COX-inhibited mice), and the closed DA of postnatal P1 and P2 mice. cGMP production and receptor affinity will be determined. Aim 3 will determine, in vivo: the response of term newborns exposed to NPs (to prevent postnatal closure); the response to fetal exposure to NP receptor antagonists (to induce fetal DA constriction); and the effect of NP antagonists on mouse models of PDA (to induce PDA constriction in neonates). These studies will provide new information on novel roles for NPs as DA mediators and identify new potential therapeutic targets for modulation of DA tone. PUBLIC HEALTH RELEVANCE: The ductus arteriosus is a fetal blood vessel whose patency is critical for survival in the womb due to its role in transmitting oxygenated blood from the placenta to fetal organs and tissues. Abnormal constriction of this vessel in the fetus or failure to properly close in the newborn is harmful, particularly in premature newborns, but the mechanisms that regulate this vessel are poorly understood. This proposal will test the hypothesis that natriuretic peptides, signaling molecules that are important for fluid balance and blood pressure control, play a significant role in regulation of the normal ductus arteriosus, and contribute to pathological states where the ductus arteriosus fails to constrict after birth.