Mechanisms of Ductus Arteriosus Regulation

描述（由申请人提供）：出生时的血管过渡依赖于肺血管的松弛和动脉导管（DA）的收缩，这在出生后不久就会发生。调节这些相反作用的机制尚未完全解决。环氧合酶（COX）衍生的前列腺素在DA调控中起关键作用。通过抑制COX抑制前列腺素合成通常导致胎儿或新生儿DA收缩。矛盾的是，一些在怀孕期间接受COX抑制剂治疗的妇女所生婴儿的DA持续通畅（PDA）而不是DA收缩。此外，缺乏COX亚型或前列腺素受体EP4基因的小鼠在出生后不久就会死于PDA。在这些条件下，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，基因缺失或长期药物抑制对前列腺素作用的破坏导致PDA的发生，这是由于指导DA成熟和敏感性的正常过程发生了改变。我们假设前列腺素信号引导了一个发育程序，该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。为了验证这种可能性，我们将检测COX-1/COX-2双缺失小鼠和缺乏EP4前列腺素受体小鼠的PDA。转基因和药理学研究将用于确定DA反应性发展的关键阶段。条件缺失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验。胞内前列腺素在DA细胞中的作用途径将被定义。在体内和体外，将通过检查DA通畅的变化或测量DA音调的变化来评估DA功能的改变。我们还将确定作为前列腺素受体信号传导潜在下游靶点的DA介质。了解DA的调节在临床上具有重要意义，因为子宫内DA过早关闭可导致胎儿受损，而PDA是最常见的先天性疾病之一，可导致心肺功能受损，并使婴儿面临慢性肺病的风险。这些研究将探讨前列腺素在发育过程中的新作用及其与其他血管活性介质的关系。

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.