Role of natriuretic peptides in the ductus arteriosus

描述（由申请方提供）：利钠肽（NP）通过其利尿、利钠和血管活性特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。患有动脉导管未闭（PDA）的婴儿由于心脏超负荷而导致ANP和BNP水平升高。NP水平在PDA治疗后很快恢复正常。这些发现表明，NP主要反映心脏状态，但我们推测，在PDA的存在下，NP的持续升高可能会增加DA松弛，并产生前馈机制，以进一步抑制DA关闭。我们的观察，NP诱导DA扩张提示进一步推测，NP管理可能是一种新的方法，以保持通畅的出生后DA。小的信息存在的作用，NP在DA的发展或作为介质的DA音。我们的初步数据表明，Npr 1，Npr 2和Npr 3受体在胎儿和新生小鼠DA中的差异表达。在胎儿和新生儿的氧条件下，分离的胎儿小鼠DA暴露于不同的NP产生剂量依赖性扩张CNP>ANP>BNP。此外，患有PDA的小鼠具有升高的循环NP水平。 我们假设：1）NP介导DA的松弛，并且可以延长出生后DA的开放性，以及2）由于PDA和继发性充血性心力衰竭引起的出生后NP水平升高有助于将DA维持在非收缩状态。这一假设将在三个具体目标中进行检验。目的1研究NPs及其受体在胎儿和新生儿DA、PDA小鼠模型和培养的DA细胞中的表达模式。目的2将在体外确定NP诱导的DA张力变化：野生型（早产与足月）小鼠、NP拮抗剂处理的野生型小鼠、Npr 1（-/-）和Npr 2（-/-）小鼠、PDA表型小鼠（考克斯-1（-/-）/考克斯-2（-/-）和COX抑制小鼠）以及出生后P1和P2小鼠的闭合DA。将测定cGMP产生和受体亲和力。目的3将在体内确定：足月新生儿暴露于NP的反应（以防止出生后闭合）;胎儿暴露于NP受体拮抗剂的反应（以诱导胎儿DA收缩）;以及NP拮抗剂对PDA小鼠模型的影响（以诱导新生儿PDA收缩）。这些研究将为NPs作为DA介质的新作用提供新的信息，并确定新的潜在治疗靶点，用于调节DA张力。 公共卫生相关性：动脉导管是胎儿的血管，由于其在将含氧血液从胎盘传输到胎儿器官和组织中的作用，其通畅性对于在子宫中的存活至关重要。胎儿中该血管的异常收缩或新生儿中未能正确闭合是有害的，特别是在早产儿中，但调节该血管的机制知之甚少。这项提议将检验以下假设：利钠肽，对体液平衡和血压控制很重要的信号分子，在正常动脉导管的调节中起重要作用，并有助于出生后动脉导管不能收缩的病理状态。

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.