Effects of Advancing Gestation and Non-Caucasian Race on Ductus Arteriosus Gene Expression.

Waleh N, Barrette AM, Dagle JM, Momany A, Jin C, Hills NK, Shelton EL, Reese J, Clyman RI
J Pediatr. 2015 167 (5): 1033-41.e2

PMID: 26265282 · PMCID: PMC4661123 · DOI:10.1016/j.jpeds.2015.07.011

OBJECTIVE - To identify genes affected by advancing gestation and racial/ethnic origin in human ductus arteriosus (DA).

STUDY DESIGN - We collected 3 sets of DA tissue (n = 93, n = 89, n = 91; total = 273 fetuses) from second trimester pregnancies. We examined four genes, with DNA polymorphisms that distribute along racial lines, to identify "Caucasian" and "non-Caucasian" DA. We used real time polymerase chain reaction to measure RNA expression of 48 candidate genes involved in functional closure of the DA, and used multivariable regression analyses to examine the relationships between advancing gestation, "non-Caucasian" race, and gene expression.

RESULTS - Mature gestation and non-Caucasian race are significant predictors for identifying infants who will close their patent DA when treated with indomethacin. Advancing gestation consistently altered gene expression in pathways involved with oxygen-induced constriction (eg, calcium-channels, potassium-channels, and endothelin signaling), contractile protein maturation, tissue remodeling, and prostaglandin and nitric oxide signaling in all 3 tissue sets. None of the pathways involved with oxygen-induced constriction appeared to be altered in "non-Caucasian" DA. Two genes, SLCO2A1 and NOS3, (involved with prostaglandin reuptake/metabolism and nitric oxide production, respectively) were consistently decreased in "non-Caucasian" DA.

CONCLUSIONS - Prostaglandins and nitric oxide are the most important vasodilators opposing DA closure. Indomethacin inhibits prostaglandin production, but not nitric oxide production. Because decreased SLCO2A1 and NOS3 expression can lead to increased prostaglandin and decreased nitric oxide concentrations, we speculate that prostaglandin-mediated vasodilation may play a more dominant role in maintaining the "non-Caucasian" patent DA, making it more likely to close when inhibited by indomethacin.

Copyright © 2015 Elsevier Inc. All rights reserved.

MeSH Terms (21)

Aorta Continental Population Groups DNA Ductus Arteriosus Ductus Arteriosus, Patent Female Gene Expression Regulation, Developmental Genotype Gestational Age Humans Indomethacin Nitric Oxide Synthase Type III Organic Anion Transporters Oxygen Polymerase Chain Reaction Polymorphism, Genetic Pregnancy Pregnancy Trimester, Second Regression Analysis Signal Transduction Time Factors

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