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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Schramm, Charlene A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Goyal, Ravi; Goyal, Dipali; Longo, Lawrence D et al. (2016) Microarray gene expression analysis in ovine ductus arteriosus during fetal development and birth transition. Pediatr Res 80:610-8
Liebowitz, Melissa; Clyman, Ronald I (2016) Antenatal Betamethasone: A Prolonged Time Interval from Administration to Delivery Is Associated with an Increased Incidence of Severe Intraventricular Hemorrhage in Infants Born before 28 Weeks Gestation. J Pediatr 177:114-120.e1
Wickremasinghe, Andrea C; Rogers, Elizabeth E; Piecuch, Robert E et al. (2012) Neurodevelopmental outcomes following two different treatment approaches (early ligation and selective ligation) for patent ductus arteriosus. J Pediatr 161:1065-72
Clyman, Ronald I; Couto, James; Murphy, Gail M (2012) Patent ductus arteriosus: are current neonatal treatment options better or worse than no treatment at all? Semin Perinatol 36:123-9
Rees, Sandra; Loeliger, Michelle; Shields, Amy et al. (2011) The effects of postnatal estrogen therapy on brain development in preterm baboons. Am J Obstet Gynecol 204:177.e8-14
Shah, Nidhi A; Hills, Nancy K; Waleh, Nahid et al. (2011) Relationship between circulating platelet counts and ductus arteriosus patency after indomethacin treatment. J Pediatr 158:919-923.e1-2
Waleh, Nahid; McCurnin, Donald C; Yoder, Bradley A et al. (2011) Patent ductus arteriosus ligation alters pulmonary gene expression in preterm baboons. Pediatr Res 69:212-6
Waleh, Nahid; Seidner, Steven; McCurnin, Donald et al. (2011) Anatomic closure of the premature patent ductus arteriosus: The role of CD14+/CD163+ mononuclear cells and VEGF in neointimal mound formation. Pediatr Res 70:332-8
Chen, S; Tacy, T; Clyman, R (2010) How useful are B-type natriuretic peptide measurements for monitoring changes in patent ductus arteriosus shunt magnitude? J Perinatol 30:780-5
Waleh, Nahid; Hodnick, Ryan; Jhaveri, Nami et al. (2010) Patterns of gene expression in the ductus arteriosus are related to environmental and genetic risk factors for persistent ductus patency. Pediatr Res 68:292-7

Showing the most recent 10 out of 63 publications