Patterns of Gene Expression in the Ductus Arteriosus Are Related to Environmental and Genetic Risk Factors for Persistent Ductus Patency

Abstract

Three independent risk factors (immature gestation, absence of antenatal glucocorticoid exposure, and presence of the rs2817399(A) allele of the gene TFAP2B) are associated with patent ductus arteriosus (PDAs) that fail to close during prostaglandin inhibition. We hypothesized that these three factors may affect a common set of genes that increase the risk of persistent PDA after birth. We studied baboon ductus from term, preterm, and glucocorticoid-treated preterm fetuses and found that both immature gestation and absence of antenatal glucocorticoid exposure decreased RNA expression of calcium-and potassium-channel genes involved in oxygen-induced constriction, and phosphodiesterase genes (that modulate cAMP/cGMP signaling). Ductus obtained from second trimester human pregnancies were genotyped for TFAP2B polymorphisms. When present, the rs2817399(A) allele also was associated with decreased expression of calcium-and potassium-channel genes. In contrast, alleles of two other TFAP2B polymorphisms, rs2817419(G) and rs2635727(T), which are not related to the incidence of PDA after birth, had no effect on RNA expression. In conclusion, three calcium-and potassium-channel genes (CACNA1G/ alpha1G, CACNB2/CaL-beta2, and KCNA2/Kv1.2) were similarly affected by each of the PDA risk factors. We speculate that these channels may play a significant role in closing the preterm ductus during prostaglandin inhibition and may be potential targets for future pharmacologic manipulations. (Pediatr Res 68: 292-297, 2010) I n contrast with the full term newborn, preterm infants frequently fail to close their ductus arteriosus after birth. Persistent ductus patency alters mesenteric blood flow, impairs pulmonary mechanics, increases the risk of pulmonary hemorrhage, and prolongs the need for mechanical ventilation (1,2).In preterm infants, persistent ductus patency appears to be the result of alterations in the balance between developmentally regulated vasoconstricting and vasodilating pathways. Alterations in prostaglandin signaling seem to account for most persistent patent ductus arteriosus (PDA); 70% of preterm infants will close their PDA when prostaglandin production is inhibited by indomethacin or ibuprofen. However, approximately 30% of PDAs are the result of factors that are independent of prostaglandin signaling. In these infants, the PDAs fail to close when prostaglandin production is inhibited (3,4). Discovering the pathways that prevent ductus closure (when prostaglandin signaling is not involved) may lead to the development of new therapeutic approaches.We recently identified three perinatal/neonatal risk factors that are independent of each other and predict the presence of PDAs that fail to close when prostaglandin signaling is inhibited (5): 1) immature gestation at birth, 2) absence of antenatal glucocorticoid exposure, and 3) racial/genetic variation (5). We hypothesized that these environmental (immature gestation and absence of antenatal glucocorticoid exposure) and genetic risk factors may be associat...

Response to Coceani et al.

“…While changes in calcium entry and sensitization appear to account for the developmental increase in ductus tension with advancing gestation, the way this is accomplished seems to vary according to the species that is studied. 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.…”

Predictors of successful closure of patent ductus arteriosus with indomethacin

“…Other pathways implicated in ductal patency and closure in experimental models and humans include decreased expression/function of calcium and potassium channels, CD14+/CD163+ mononuclear cell adhesion to the ductal lumen (for neointimal growth), and isoprostane-mediated signaling via EP4 receptors. [20][21][22][23] Candidate gene studies have identified specific gene polymorphisms associated with PDA in human preterm infants, with polymorphisms in the TFAP2B and TNF receptor-associated factor 1 genes reported to be associated with the presence of a PDA. 20 Previously published reports have primarily focused on the platelet counts during the first few days of life.…”

Relationship between Circulating Platelet Counts and Ductus Arteriosus Patency after Indomethacin Treatment

“…These sick, preterm infants are the same babies that are likely to have delayed ductus closure after birth (24). We speculate that rather than contributing to PDA closure, platelet counts that remain in the highest quintile are merely an independent, surrogate marker of neonatal well being and of the presence of developmental factors that promote ductus closure after birth (25). …”