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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077395-05
Application #
7751829
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Schramm, Charlene A
Project Start
2006-01-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
5
Fiscal Year
2010
Total Cost
$372,621
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Shelton, Elaine L; Ector, Gerren; Galindo, Cristi L et al. (2014) Transcriptional profiling reveals ductus arteriosus-specific genes that regulate vascular tone. Physiol Genomics 46:457-66
Vucovich, Megan M; Cotton, Robert B; Shelton, Elaine L et al. (2014) Aminoglycoside-mediated relaxation of the ductus arteriosus in sepsis-associated PDA. Am J Physiol Heart Circ Physiol 307:H732-40
Shelton, Elaine L; Poole, Stanley D; Reese, Jeff et al. (2013) Omental grafting: a cell-based therapy for blood vessel repair. J Tissue Eng Regen Med 7:421-33
Cotton, Robert B; Shah, Lisa P; Poole, Stanley D et al. (2013) Cimetidine-associated patent ductus arteriosus is mediated via a cytochrome P450 mechanism independent of H2 receptor antagonism. J Mol Cell Cardiol 59:86-94
Chen, Jian-Xiong; O'Mara, Patrick W; Poole, Stanley D et al. (2012) Isoprostanes as physiological mediators of transition to newborn life: novel mechanisms regulating patency of the term and preterm ductus arteriosus. Pediatr Res 72:122-8
Chen, Jian-Xiong; Zeng, Heng; Reese, Jeff et al. (2012) Overexpression of angiopoietin-2 impairs myocardial angiogenesis and exacerbates cardiac fibrosis in the diabetic db/db mouse model. Am J Physiol Heart Circ Physiol 302:H1003-12
Stoller, Jason Z; Demauro, Sara B; Dagle, John M et al. (2012) Current Perspectives on Pathobiology of the Ductus Arteriosus. J Clin Exp Cardiolog 8:
Johnston, Palmer G; Gillam-Krakauer, Maria; Fuller, M Paige et al. (2012) Evidence-based use of indomethacin and ibuprofen in the neonatal intensive care unit. Clin Perinatol 39:111-36
Cotton, Robert; Suarez, Sandra; Reese, Jeff (2012) Unexpected extra-renal effects of loop diuretics in the preterm neonate. Acta Paediatr 101:835-45
McElroy, Steven J; Prince, Lawrence S; Weitkamp, Jörn-Hendrik et al. (2011) Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 301:G656-66

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