Effects of Advancing Gestation and Non-Caucasian Race on Ductus Arteriosus Gene Expression.
OBJECTIVE
To identify genes affected by advancing gestation and racial/ethnic origin in human ductus arteriosus (DA).


METHODS
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.
Biosciences Division, SRI International, Menlo Park, CA.
Nahid
N
Waleh
Cardiovascular Research Institute and Department of Pediatrics, University of California San Francisco, San Francisco, CA.
Anne Marie
AM
Barrette
Department of Pediatrics, University of Iowa, Iowa City, IA.
John M
JM
Dagle
Department of Pediatrics, University of Iowa, Iowa City, IA.
Allison
A
Momany
Department of Neurology, University of California San Francisco, San Francisco, CA.
Chengshi
C
Jin
Department of Neurology, University of California San Francisco, San Francisco, CA.
Nancy K
NK
Hills
Department of Pediatrics, Vanderbilt University, Nashville, TN.
Elaine L
EL
Shelton
Department of Pediatrics, Vanderbilt University, Nashville, TN.
Jeff
J
Reese
Cardiovascular Research Institute and Department of Pediatrics, University of California San Francisco, San Francisco, CA. Electronic address: clymanr@peds.ucsf.edu.
Ronald I
RI
Clyman
D001011:Aorta / Q000473:pathology; D004247:DNA; D004373:Ductus Arteriosus / Q000196:embryology / Q000378:metabolism*; D004374:Ductus Arteriosus, Patent / Q000188:drug therapy / Q000208:ethnology* / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D005865:Gestational Age; D006801:Humans; D007213:Indomethacin / Q000627:therapeutic use; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D044469:Racial Groups; D012044:Regression Analysis; D015398:Signal Transduction; D013997:Time Factors
D027361:Organic Anion Transporters; C503526:SLCO2A1 protein, human; D004247:DNA; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D010100:Oxygen; D007213:Indomethacin