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.

出生时的血管过渡依赖于肺血管的舒张和肺动脉的收缩。 动脉导管（DA），这发生在分娩后不久。调节这些对立的机制 影响尚未完全解决。环氧合酶（考克斯）衍生的类胡萝卜素在DA中起关键作用 调控通过考克斯抑制剂抑制前列腺素合成通常导致前列腺增生的收缩。 胎儿或新生儿DA。奇怪的是，一些在怀孕期间接受考克斯抑制剂的妇女， DA持续通畅（PDA）而非DA狭窄的婴儿。此外，小鼠在遗传上 两种考克斯同种型或EP 4前列腺素受体都缺乏的婴儿在出生后不久死于PDA。的 在这些条件下使DA对收缩刺激不敏感的机制是未知的。我们 初步数据表明，前列腺素的作用，通过基因缺失或延长中断， 由于指导成熟的正常过程的改变，药物抑制导致PDA， 我们假设前列腺素信号传导指导发育程序， 在妊娠后期和出生后逐渐增加DA对其他血管活性介质的反应性。为了验证这一 可能的是，考克斯-1/考克斯-2双无效小鼠和缺乏EP 4前列腺素受体的小鼠的PDA将 接受检查。转基因和药理学研究将被用来定义的关键阶段， 开发DA响应性。条件性缺失EP 4和考克斯-1/考克斯-2的小鼠将有助于 确定前列腺素在DA内皮平滑肌中作用的时间和来源 将在细胞培养和转基因实验中检查相互作用。细胞内 将定义DA细胞中的前列腺素作用。将在体内和体内评价DA功能的改变。 通过检查DA开放性的变化或测量DA张力的变化来体外测定。我们还将确定DA 介体是前列腺素受体信号传导的潜在下游靶点。了解DA 调节在临床上是重要的，因为子宫内DA的过早闭合可导致胎儿受损， 而动脉导管未闭是最常见的先天性疾病之一，导致心肺功能受损 并使婴儿面临慢性肺病的风险。这些研究将探讨新的作用， 以及它们在发育过程中与其他血管活性介质的关系。