Mechanisms of Ductus Arteriosus Regulation

动脉导管调节机制

• 批准号: 7036153
• 负责人: John Jeffrey Reese
• 金额: $ 36.81万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7036153
• 关键词: angiogenesis; artery; biological signal transduction; embryo /fetus; embryogenesis; gene targeting; genetically modified animals; inhibitor /antagonist; laboratory mouse; muscle tone; patent ductus arteriosus; polymerase chain reaction; prostaglandin endoperoxide synthase; prostaglandin receptor; prostaglandins; receptor expression; smooth muscle; tissue /cell culture; vascular endothelium

DESCRIPTION (provided by applicant): 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 and source of prostaglandin actions in the DA. DA endothelial - 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.

描述（由申请人提供）：出生时的血管转变取决于肺血管系统的松弛和动脉导管（DA）的收缩，这在分娩后不久就会发生。调节这些相反作用的机制尚未完全解决。环加氧酶 (COX) 衍生的前列腺素在 DA 调节中发挥着关键作用。通过 COX 抑制来抑制前列腺素合成通常会导致胎儿或新生儿 DA 收缩。矛盾的是，一些在怀孕期间接受 COX 抑制剂的女性生下的婴儿是 DA 持续通畅 (PDA)，而不是 DA 收缩。此外，COX亚型或EP4前列腺素受体基因缺陷的小鼠在出生后不久就会死亡并患有PDA。在这些条件下使 DA 对收缩刺激不敏感的机制尚不清楚。我们的初步数据表明，由于指导 DA 成熟和敏感性的正常过程发生改变，基因缺失或长期药理学抑制导致前列腺素作用中断，从而导致 PDA。我们假设前列腺素信号传导指导一个发育程序，该程序在妊娠后期和出生后逐渐灌输 DA 对其他血管活性介质的反应性。为了测试这种可能性，将检查 COX-1/COX-2 双无效小鼠和缺乏 EP4 前列腺素受体的小鼠的 PDA。转基因和药理学研究将用于确定 DA 反应性发育的关键阶段。有条件删除 EP4 和 COX-1/COX-2 的小鼠将有助于确定 DA 中前列腺素作用的时间和来源。 DA 内皮-平滑肌相互作用将在细胞培养和转基因实验中进行检查。 DA 细胞中细胞内前列腺素作用的途径将被定义。通过检查 DA 通畅性的变化或测量 DA 音调的变化，可以在体内和体外评估 DA 功能的改变。我们还将鉴定作为前列腺素受体信号传导潜在下游靶标的 DA 介质。了解 DA 调节具有临床重要意义，因为 DA 在子宫内过早关闭可能会导致胎儿受损，而 PDA 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慢性肺病的风险。这些研究将探讨前列腺素的新作用及其在发育过程中与其他血管活性介质的关系。