Mechanisms of Ductus Arteriosus Regulation
Principal Investigator: JOHN JEFFREY REESE
Abstract: 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.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT
- Inhibition of cyclooxygenase isoforms in late- but not midgestation decreases contractility of the ductus arteriosus and prevents postnatal closure in miceJeff Reese
Department of Pediatrics, Vanderbilt University Medical Center, 1125 MRB IV Bldg, 2215 B Garland Avenue, Nashville, TN 37232 0656, USA
Am J Physiol Regul Integr Comp Physiol 291:R1717-1723. 2006..They are consistent with a novel role for prostaglandins in ductus arteriosus contractile development...
- Isoprostanes as physiological mediators of transition to newborn life: novel mechanisms regulating patency of the term and preterm ductus arteriosusJian xiong Chen
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, USA
Pediatr Res 72:122-8. 2012..We hypothesized that isoprostanes regulate ductus arteriosus (DA) function during postnatal vascular transition...
- Unexpected extra-renal effects of loop diuretics in the preterm neonateROBERT COTTON
Department of Pediatrics, Division of Neonatology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Acta Paediatr 101:835-45. 2012..Loop diuretics also affect the central nervous system through modulation of the GABA-A chloride channel...
- Cimetidine-associated patent ductus arteriosus is mediated via a cytochrome P450 mechanism independent of H2 receptor antagonismRobert B Cotton
Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr Children s Hospital at Vanderbilt, Nashville, TN 37232, USA
J Mol Cell Cardiol 59:86-94. 2013..These studies show that antacids and other compounds with CYP inhibitory properties pose a significant and previously unrecognized risk for PDA in critically ill newborn infants...
- Inadvertent relaxation of the ductus arteriosus by pharmacologic agents that are commonly used in the neonatal periodJeff Reese
Department of Pediatrics, Monroe Carrell Jr Children s Hospital at Vanderbilt, Vanderbilt University School of Medicine, Nashville, TN, USA
Semin Perinatol 34:222-30. 2010....
- Ibuprofen treatment for closure of patent ductus arteriosus is not associated with increased risk of neuropathologyMichelle Loeliger
Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Victoria 3010, Australia
Pediatr Res 68:298-302. 2010..No overt cerebellar alterations were observed in either group. Ibuprofen treatment for PDA closure in the preterm baboon neonate is not associated with any increased risk of neuropathology or alterations to brain growth and development...
- Chronic in utero cyclooxygenase inhibition alters PGE2-regulated ductus arteriosus contractile pathways and prevents postnatal closureJeff Reese
Department of Pediatrics, Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37232, USA
Pediatr Res 66:155-61. 2009..Alterations in these effectors may explain the increased risk of patent ductus arteriosus (PDA) after in utero COX inhibition...
- Overexpression of angiopoietin-2 impairs myocardial angiogenesis and exacerbates cardiac fibrosis in the diabetic db/db mouse modelJian xiong Chen
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA
Am J Physiol Heart Circ Physiol 302:H1003-12. 2012..Our data demonstrate that Ang-2 increases endothelial apoptosis, sensitizes myocardial microvascular inflammation, and promotes cardiac fibrosis and thus contributes to loss of capillary density in diabetic diseases...
- Evidence-based use of indomethacin and ibuprofen in the neonatal intensive care unitPalmer G Johnston
Neonatal Perinatal Medicine, Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, 2200 Children s Way, Nashville, TN 37232 9544, USA
Clin Perinatol 39:111-36. 2012..Despite the call for restrained use of each drug, the most immature infants are likely to need pharmacologic approaches to reduce high-grade IVH, avoid the need for PDA ligation, and preserve the opportunity for an optimal outcome...
- Oxygen-induced tension in the sheep ductus arteriosus: effects of gestation on potassium and calcium channel regulationNahid Waleh
Pharmaceutical Discovery Division, SRI International, Menlo Park, California 94025, USA
Pediatr Res 65:285-90. 2009..Super-physiologic oxygen concentrations eliminate the difference in tensions between the two age groups...
- Regulation of the fetal mouse ductus arteriosus is dependent on interaction of nitric oxide and COX enzymes in the ductal wallJeff Reese
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232 0656, USA
Prostaglandins Other Lipid Mediat 88:89-96. 2009....
- Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitisSteven J McElroy
Dept of Pediatrics, Div of Neonatology, Nashville, TN 37232 0696, USA
Am J Physiol Gastrointest Liver Physiol 301:G656-66. 2011....