In the full term neonate, the ductus arteriosus (DA) constricts rapidly after delivery in order to separate the pulmonary from systemic circulations. In the premature infant, the DA frequently remains open after birth. Failure of the DA to close after birth results in significant morbidity: necrotizing enterocolitis and a prolonged need for mechanical ventilation. As many as 70% of newborns delivered prior to 28 weeks gestation will require some form of therapy to close their patent DA. During the past 5 years we found that postnatal ductus constriction produces profound ischemia in the inner DA wall. This profound ischemia is essential for initiating the anatomic remodeling that permanently closes the DA. The preterm newborn DA fails to develop the same degree of DA wall ischemia as the full term newborn and fails to remodel its wall after birth. Hypoxic ischemia in the DA wall is determined by the degree of postnatal constriction of the DA. In the preterm DA, the primary reason for its persistent patency and inadequate anatomic remodeling is its failure to develop tight constriction after birth. When compared with the full term DA, the preterm DA has a decreased ability to develop active tension and an increased sensitivity to vasodilators like Prostaglandin E2 (PGE2). In this application we plan to identify the mechanisms that enable the full term DA to produce tight constriction after birth, and to determine how they differ from those in the preterm DA. We hypothesize that alterations in the ability of the preterm DA to respond to and regulate the entry and removal of extracellular calcium from the DA wall are primarily responsible for its decreased ability to develop active tension and its increased sensitivity to PGE2. The studies proposed in this application will examine isometric contractility, calcium signaling, and cAMP regulation in the preterm and full term DA. They will study the DA both in vivo and in vitro using displacement binding assays, Western immunoblots, and Real Time PCR to examine changes in RNA, protein expression, and receptor binding. These studies should increase our understanding of the mechanisms that prevent the preterm DA from closing and remodeling after birth.
Showing the most recent 10 out of 65 publications
