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DA closure is crucial for the transition from fetal to neonatal life. This closure is supported by changes to the DA's signaling and structural properties that distinguish it from neighboring vessels. Examining transcriptional differences between these vessels is key to identifying genes or pathways responsible for DA closure. Several microarray studies have explored the DA transcriptome in animal models but varied experimental designs have led to conflicting results. Thorough transcriptomic analysis of the human DA has yet to be performed. A clear picture of the DA transcriptome is key to guiding future research endeavors, both to allow more targeted treatments in the clinical setting, and to understand the basic biology of DA function. In this review, we use a cross-species cross-platform analysis to consider all available published rodent microarray data and novel human RNAseq data in order to provide high priority candidate genes for consideration in future DA studies.

Introduction Development of the outflow tract (OFT) of the heart is complex, involving input from several embryologically distinct cell populations including cardiac progenitors from the second heart field, cardiac neural [...], Notch signaling is vital for proper cardiovascular development and function in both humans and animal models. Indeed, mutations in either JAGGED or NOTCH cause congenital heart disease in humans and NOTCH mutations are associated with adult valvular disease. Notch typically functions to mediate developmental interactions between adjacent tissues. Here we show that either absence of the Notch ligand Jagged1 or inhibition of Notch signaling in second heart field tissues results in murine aortic arch artery and cardiac anomalies. In mid-gestation, these mutants displayed decreased Fgf8 and Bmp4 expression. Notch inhibition within the second heart field affected the development of neighboring tissues. For example, faulty migration of cardiac neural crest cells and defective endothelial-mesenchymal transition within the outflow tract endocardial cushions were observed. Furthermore, exogenous Fgf8 was sufficient to rescue the defect in endothelial-mesenchymal transition in explant assays of endocardial cushions following Notch inhibition within second heart field derivatives. These data support a model that relates second heart field, neural crest, and endocardial cushion development and suggests that perturbed Notch-Jagged signaling within second heart field progenitors accounts for some forms of congenital and adult cardiac disease.

Background: Prophylactic indomethacin reduces the risk of severe intraventricular hemorrhage (IVH) but does not reduce death or neurodevelopmental impairment (NDI) among extremely low birth weight (ELBW) infants. Some investigators have suggested that prophylactic indomethacin may have a greater treatment effect on severe IVH among infants at high risk for severe IVH. Objective: To determine whether the relative treatment effects of prophylactic indomethacin on severe IVH and the composite outcome of death or NDI vary based on the risk of severe IVH. Methods: Post hoc analysis of the Trial of Indomethacin Prophylaxis in Preterms (TIPP). We generated a model to predict the risk for severe IVH based on gestational age, birth weight, antenatal steroids, delivery mode, outborn status, sex, and 5-min Apgar score, and we divided the TIPP participants into risk quartiles. We used logistic regression to determine the adjusted odds ratios (aOR) of severe IVH and death or NDI based on indomethacin treatment for each quartile. Results: The relative treatment effects of prophylactic indomethacin on severe IVH did not vary based on the predicted risk of severe IVH: quartile 1: aOR 0.68 (95% confidence interval [CI] 0.19-2.37); quartile 2: aOR 0.61 (95% CI 0.27-1.42); quartile 3: aOR 0.63 (95% CI 0.31-1.31); quartile 4: aOR 0.58 (95% CI 0.32-1.05). The relative treatment effect of prophylactic indomethacin on death or NDI did not vary significantly between quartiles. Conclusions: These findings do not support selective prophylactic indomethacin treatment to improve long-term outcomes of ELBW infants at high risk for severe IVH. [ABSTRACT FROM AUTHOR]

Jun is a highly conserved member of the multimeric activator protein 1 transcription factor complex and plays an important role in human cancer where it is known to be critical for proliferation, cell cycle regulation, differentiation, and cell death. All of these biological functions are also crucial for embryonic development. Although all Jun null mouse embryos die at mid-gestation with persistent truncus arteriosus, a severe cardiac outflow tract defect also seen in human congenital heart disease, the developmental mechanisms are poorly understood. Here we show that murine Jun is expressed in a restricted pattern in several cell populations important for cardiovascular development, including the second heart field, pharyngeal endoderm, outflow tract and atrioventricular endocardial cushions and post-migratory neural crest derivatives. Several genes, including Isl1, molecularly mark the second heart field. Isl1 lineages include myocardium, smooth muscle, neural crest, endocardium, and endothelium. We demonstrate that conditional knockout mouse embryos lacking Jun in Isl1-expressing progenitors display ventricular septal defects, double outlet right ventricle, semilunar valve hyperplasia and aortic arch artery patterning defects. In contrast, we show that conditional deletion of Jun in Tie2-expressing endothelial and endocardial precursors does not result in aortic arch artery patterning defects or embryonic death, but does result in ventricular septal defects and a low incidence of semilunar valve defects, atrioventricular valve defects and double outlet right ventricle. Our results demonstrate that Jun is required in Isl1-expressing progenitors and, to a lesser extent, in endothelial cells and endothelial-derived endocardium for cardiovascular development but is dispensable in both cell types for embryonic survival. These data provide a cellular framework for understanding the role of Jun in the pathogenesis of congenital heart disease. [ABSTRACT FROM AUTHOR]

The ductus arteriosus (DA) shunts blood away from the lungs during fetal life, but at birth this shunt is no longer needed and the vessel rapidly constricts. Postnatal persistence of the DA, patent ductus arteriosus (PDA), is predominantly a detrimental condition for preterm infants but is simultaneously a condition required to maintain systemic blood flow for infants born with certain severe congenital heart defects. Although PDA in preterm infants is associated with significant morbidities, there is controversy regarding whether PDA is truly causative. Despite advances in our understanding of the pathobiology of PDA, the optimal treatment strategy for PDA in preterm infants is unclear. Here we review recent studies that have continued to elucidate the fundamental mechanisms of DA development and pathogenesis.