Microarray gene expression analysis in ovine ductus arteriosus during fetal development and birth transition

Abstract

BACKGROUND Patent ductus arteriosus (PDA) in the newborn is the most common congenital heart anomaly and is significantly more common in preterm infants. Contemporary pharmacological treatment is effective in only 70–80% of the cases. Moreover, indomethacin or ibuprofen, which are used to close a PDA may be accompanied by serious side effects in premature infants. To explore the novel molecular pathways, which may be involved in the maturation and closure of the ductus arteriosus (DA), we used fetal and neonatal sheep to test the hypothesis that maturational development of DA is associated with significant alterations in specific mRNA expression. METHODS We conducted oligonucleotide microarray experiments on the isolated mRNA from DA and ascending aorta from three study groups (premature fetus—97 ± 0 d, near-term fetus—136 ± 0.8 d, and newborn lamb—12 ± 0 h). We compared the alterations in mRNA expression in DA and aorta to identify genes specifically involved in DA maturation. RESULTS Results demonstrate significant changes in wingless–integrin1, thrombospondin 1, receptor activator of nuclear factor-kappa B, nitric oxide synthase, and retinoic acid receptor activation signaling pathways. CONCLUSION We conclude that these pathways may play an important role during both development and postnatal DA closure and warrant further investigation.

Ductus arteriosus: gene profile for fetal maturation versus postnatal closure

“…Otherwise, our past work (3) aligns itself with that of Goyal et al (1) in highlighting the role of certain genes in promoting the maturation of the ductus. In particular, we may add support to the proposed involvement of the Wnt-planar cell polarity/Wnt-β-catenin pathways by showing not only the presence of genes coincident with the listing of Goyal et al (1), but also the likely contribution of a separate cohort of functionally allied genes ( Table 1).…”

“…Cadherin 1 Data from our study (3), with entries in bold being common to the study of Goyal et al (1). Note that the two studies shared, in the whole, the preferential expression of 11 genes.…”

“…In conclusion, the study of Goyal et al (1) sheds better light on the maturation process of the ductus, but is seemingly amiss in documenting events that underlie the functional closure of the vessel.…”

“…In the same study, it has also been demonstrated that RhoB stands out as a prominent element in a hierarchical clustering of genes in the neonatal ductus. A possible explanation for this apparent incongruence may be found in the analytical approach of Goyal et al (1), where a paired comparison of duct specimens at different developmental stages (i.e., preterm versus term/term versus neonate) might have yielded a final pool of genes in which the expression profile for antenatal maturation outweighs features proper of the functional closure at birth.…”

Response to Coceani et al.

“…For example, using quantitative PCR, we previously found that with advancing gestation RhoB expression is significantly increased in human (5) and mouse (unpublished results) ductussimilar to what Dr. Coceani's laboratory observed in fetal rats. However, in sheep (3,4)) and baboon (unpublished results) ductus there was no increase or decrease in RhoB expression. Although we have not examined the expression of calmodulin by quantitative PCR among the different species, it is quite possible that its expression might also vary depending on the species studied.…”