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）：出生时的血管过渡依赖于分娩后不久发生的肺血管舒张和动脉导管（DA）收缩。调节这些对立效应的机制尚未完全解决。环氧合酶（考克斯）衍生的木兰素在DA调节中起关键作用。通过考克斯抑制剂抑制前列腺素合成通常导致胎儿或新生儿DA的收缩。特别是，一些在妊娠期间接受考克斯抑制剂的妇女所产婴儿的DA（PDA）持续通畅，而不是DA收缩。此外，遗传上缺乏两种考克斯亚型或EP 4前列腺素受体的小鼠在出生后不久死于PDA。在这些条件下，使DA幼稚的收缩刺激的机制是未知的。我们的初步数据表明，破坏前列腺素行动的遗传缺失或长期的药理学抑制导致PDA由于正常过程中的改变，指导成熟和敏感性的DA。我们假设，前列腺素信号传导指导的发展计划，灌输反应的DA其他血管活性介质在妊娠后期和出生后。为了测试这种可能性，将检查考克斯-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。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。EP 4和考克斯-1/考克斯-2条件性缺失的小鼠将有助于确定DA中前列腺素作用的时间和来源。将在细胞培养和转基因实验中检查DA内皮-平滑肌相互作用。将确定DA细胞中细胞内前列腺素作用的途径。通过检查DA通畅性的变化或测量DA张力的变化，在体内和体外评价DA功能的变化。我们还将确定DA介质是前列腺素受体信号传导的潜在下游靶点。了解DA调节在临床上很重要，因为子宫内DA的过早闭合可能导致胎儿受损，而PDA是最常见的先天性疾病之一，导致心肺功能受损，并使婴儿处于慢性肺部疾病的风险中。这些研究将探讨新的作用，为三尖杉酯碱及其与其他血管活性介质在发展过程中的关系。