Mechanisms of Ductus Arteriosus Regulation

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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.