Estrogen (E) has nitric oxide (NO)-mediated effects in certain vascular beds, and fetal E levels rise acutely with parturition, suggesting that E may be involved in NO-mediated pulmonary vasodilation at birth. We tested the hypothesis that E acutely stimulates NO synthase (NOS) activity in ovine fetal pulmonary artery endothelial cells (PAEC) by measuring L-[3H]arginine conversion to L-[3H]citrulline in intact cells. NOS activity in the presence of 17 beta-estradiol (E2 beta) rose in a dose-dependent manner, increasing 70-100%, with a threshold concentration of 10(-10) M. This effect was detectable within 5 min of E2 beta exposure, and the maximal response was comparable to that obtained with acetylcholine, which had a threshold concentration of 10(-8) M. Ca2+ removal completely inhibited E2 beta-stimulated NOS activity, and activity with E2 beta and the Ca2+ ionophore A-23187 was not additive. In addition, the expression of the endothelial isoform of NOS (eNOS) was not altered, and the inducible and neuronal NOS isoforms were not detected by immunoblot analysis. These findings indicate that E2 beta acutely stimulates eNOS by Ca2+ influx. Furthermore, E2 beta-stimulated NOS activity was fully inhibited by the E receptor (ER) antagonists tamoxifen and ICI-182,780, and ER mRNA expression was evident in reverse transcription-polymerase chain reaction assays. Thus E acutely stimulates eNOS activity in fetal PAEC via the activation of endothelial ER and increases in intracellular Ca2+.

Hemodynamic decompensation occurred in 28% of patients after PDA ligation, resulting in a significantly higher mortality. Younger patients requiring higher ventilator support are most likely to develop hemodynamic decompensation.

Isolated coarctation of the aorta (CoA) is estimated by the Centers for Disease Control and Prevention to account for 4%-6% of all congenital heart disease (CHD) in the United States, with a reported prevalence of ~4 per 10 000 live births. Prenatal recognition of coarctation is important as it may improve neonatal survival and reduce morbidity. However, despite advances in imaging and the trend toward detailed aortic arch assessment as part of a comprehensive fetal echocardiogram, isolated CoA may still elude prenatal detection, with potentially lethal consequences if the diagnosis is not suspected and the patent ductus arteriosus (PDA) closes spontaneously in postnatal life. The purpose of this review is to outline the methods of antenatal aortic arch evaluation in the current era, discuss "red flags" that raise the suspicion for CoA, including associated anomalies and serve as a repository of the most up to date information regarding its diagnosis in utero and its perinatal management. Other aortic arch abnormalities, such as interrupted aortic arch, or CoA associated with complex single ventricles, are not included in this review.

Endothelium-derived nitric oxide (NO) generated by endothelial NO synthase (eNOS) is critically involved in pulmonary vasodilation during cardiopulmonary transition at birth. Inhaled NO therapy has recently been considered for patients with persistent pulmonary hypertension of the newborn (PPHN). To better understand the mechanisms regulating NO synthesis in the developing pulmonary circulation and the possible ramifications of NO therapy, studies were performed with early passage ovine fetal intrapulmonary artery endothelial cells (PAEC) to determine whether NO directly modulates eNOS expression. To examine the effects of exogenous NO, PAEC were treated with the NO donor spermine NONOate or the parent compound spermine. Exogenous NO caused increases in eNOS protein expression and NOS enzymatic activity that were detectable within 16 h of exposure. In contrast, the inhibition of endogenous NO production with nitro-L-arginine-methyl ester (L-NAME) caused a reduction in eNOS protein expression that was evident within 8 h. Paralleling the changes in eNOS protein, eNOS messenger RNA (mRNA) abundance was upregulated by exogenous NO and downregulated by L-NAME, suggesting that NO modulation of eNOS expression involves processes at the level of gene transcription or mRNA stability. Thus, in fetal PAEC there is positive-feedback regulation of eNOS expression by both exogenous and endogenous NO. These findings suggest that difficulties with transient effectiveness or prolonged requirements for NO therapy in certain PPHN patients are not due to declines in eNOS expression. Further, conditions such as fetal hypoxemia that impair PAEC NO production may attenuate eNOS expression through this mechanism, thereby contributing to the pathogenesis of PPHN.