Mechanisms of Ductus Arteriosus Regulation

动脉导管调节机制

• 批准号: 7839511
• 负责人: John Jeffrey Reese
• 金额: $ 15.01万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7839511
• 关键词: Acute; Address; Aorta; Birth; Blood Vessels; Cardiopulmonary; Cell Communication; Cell Culture Techniques; Cells; Chronic lung disease; Congenital Disorders; Coxibs; Cyclooxygenase Inhibitors; Data; Development; Ductus Arteriosus; Electron Microscopy; Endocrine; Exposure to; Failure; Fetal Development; Genetic; Human; Hyperbaric Oxygenation; In Vitro; Indomethacin; Infant; Knock-out; Knockout Mice; Legal patent; Ligands; Ligation; Lung; Measures; Mediating; Mediator of activation protein; Modeling; Mus; Muscle; Neonatal; Newborn Infant; Operative Surgical Procedures; Patent Ductus Arteriosus; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Positioning Attribute; Pregnancy; Premature Infant; Premature Labor; Process; Prostaglandin E Receptor; Prostaglandin Receptor; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Isoforms; Pulmonary artery structure; Receptor Signaling; Regulation; Relaxation; Risk; Role; Shunt Device; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Source; Staging; Stimulus; Testing; Time; Tissues; Transgenic Organisms; Vasoconstrictor Agents; Vasodilation; Withdrawal; Woman; clinically significant; constriction; critical period; cyclooxygenase 1; cyclooxygenase 2; expectation; fetal; human WFDC2 protein; in utero; in vivo; novel; postnatal; premature; prenatal exposure; prevent; programs; prostaglandin EP4 receptor; pup; receptor; research study; response; stem; vascular bed

Vascular transition at birth is dependent on relaxation of the pulmonary vasculature and constriction of the ductus arteriosus (DA), which occur soon after delivery. The mechanisms that regulate these opposing effects are not fully resolved. Cyclooxygenase (COX)-derived prostaglandins play a critical role in DA regulation. Suppression of prostaglandin synthesis by COX inhibition usually results in constriction of the fetal or neonatal DA. Paradoxically, some women who receive COX inhibitors during pregnancy have infants with persistent patency of the DA (PDA) instead of DA constriction. In addition, mice genetically deficient for both COX isoforms or for the EP4 prostaglandin receptor die soon after birth with a PDA. The mechanisms that render the DA naive to contractile stimuli under these conditions are unknown. Our preliminary data suggests that disruption of prostaglandin actions by genetic deletion or prolonged pharmacologic inhibition results in PDA due to alterations in the normal process that directs maturation and sensitivity of the DA. We hypothesize that prostaglandin signaling directs a developmental program that instills responsiveness of the DA to other vasoactive mediators later in gestation and after birth. To test this possibility, the PDA of COX-1/COX-2 double null mice and mice lacking the EP4 prostaglandin receptor will be examined. Transgenic and pharmacological studies will be used to define the critical stage of development for DA responsiveness. Mice with conditional deletion of EP4 and COX-1/COX-2 will help determine the timing andsource of prostaglandin actions in the DA. DAendothelial - smooth muscle interactions will be examined in cell culture and transgenic experiments. Pathways for intracellular prostaglandin actions in DA cells will be defined. Alterations in DA function will be evaluated in vivo and in vitro by examining changes in DA patency or measuring changes in DA tone. We will also identify DA mediators that are potential downstream targets of prostaglandin receptor signaling. Understanding DA regulation is clinically important since premature closure of the DA in utero can result in fetal compromise, while a PDA is one of the most frequent congenital disorders, leading to impaired cardiopulmonary function and placing infants at risk for chronic lung disease. These studies will examine new roles for prostaglandins and their relationship with other vasoactive mediators during development.

出生时的血管转换取决于肺血管的松弛和收缩 动脉导管(DA)，发生在分娩后不久。调节这些对立的机制 影响尚未完全解决。环氧合酶(COX)衍生的前列腺素在DA中起关键作用 监管。通过抑制COX抑制前列腺素合成通常会导致细胞收缩 胎儿或新生儿DA。矛盾的是，一些在怀孕期间接受环氧合酶抑制剂的女性 DA持续通畅(PDA)而不是DA狭窄的婴儿。此外，小鼠的基因 缺乏COX亚型或EP4前列腺素受体的患者在出生后不久就会死于PDA。这个 在这些情况下，使DA对收缩刺激幼稚的机制尚不清楚。我们的 初步数据表明，通过基因缺失或延长而破坏前列腺素的作用 药物抑制导致动脉导管未闭，是由于正常的成熟和 地区检察官的敏感性。我们假设前列腺素信号引导一种发育程序 在妊娠后期和出生后灌输DA对其他血管活性介质的反应性。为了测试这一点 COX-1/COX-2双缺失小鼠和EP4前列腺素受体缺失小鼠的PDA可能 接受检查。转基因和药理学研究将被用来定义 发展发展议程的响应性。条件缺失EP4和COX-1/COX-2的小鼠将有所帮助 在DA中确定前列腺素作用的时间和来源。血管内皮细胞--平滑肌 相互作用将在细胞培养和转基因实验中进行检验。细胞内途径 前列腺素在DA细胞中的作用将被定义。DA功能的改变将在体内和体内进行评估 通过检测DA通畅度的变化或测量DA音调的变化来进行体外实验。我们还将确定地区检察官 作为前列腺素受体信号传导的潜在下游靶点的介体。了解DA 调控在临床上很重要，因为在子宫内过早关闭DA可能会导致胎儿受损， 而掌上电脑是最常见的先天性疾病之一，会导致心肺功能受损 并使婴儿面临患慢性肺部疾病的风险。这些研究将考察前列腺素的新作用。 以及它们在发育过程中与其他血管活性介质的关系。