3, 4 This constriction within the first hours after birth is interpreted as the functional closure of the DA and has been extensively examined. 3, 4 Around the same time, an increase in arterial oxygen tension and a decrease in blood pressure within the DA lumen also play a critical role in DA constriction. The resulting rapid decline in PGE 2 triggers DA constriction. 3 At the time of birth, the placental source is eliminated and the circulating PGE 2 begins to be metabolized in the now functioning lungs. In utero, vasodilation is primarily maintained by circulating prostaglandin E 2 (PGE 2), which is produced by the placenta and is the most potent vasodilatory lipid mediator of the DA. Therefore, it is important to understand the precise mechanisms by which closure of the DA is regulated.

2 In contrast, patency of the DA can be essential for patients with complex congenital heart diseases in which the systemic or pulmonary circulation is dependent on the passage of blood through the DA. 1 Although patency of the DA is required for fetal survival, PDA is a major cause of morbidity and mortality in premature infants, because it leads to severe complications including pulmonary hypertension, right ventricular dysfunction, postnatal infections, and respiratory failure. It is particularly common in premature infants with birthweight <1000вЂ‰g, in whom the incidence of PDA has been estimated to be 40%.

In premature infants, however, the DA often remains patent after the neonatal period this condition is termed persistent patency of the DA (PDA). In full-term infants, this fetal structure normally closes during the first few days after birth. The ductus arteriosus (DA), which shunts blood away from the high-resistance pulmonary circulation during fetal life, is indispensable for normal fetal development. Understanding the physiological role of PGE 2 in DA remodeling could enable more effective regulation of PDA, both in isolation and in the context of congenital cardiac anomalies. Signals that are downstream of PGE 2-EP4, such as cyclic AMP (cAMP)-protein kinase A (PKA), exchange protein activated by cAMP (Epac), phospholipase C, and Wnt/ОІ-catenin, may be involved in the regulation of intimal thickening, elastogenesis, and contraction-related genes. Emerging evidence from studies using pharmacological approaches and genetically modified mice suggests that, in addition to its vasodilatory effect, this chronic exposure to PGE 2 promotes DA-specific anatomical and molecular remodeling through EP4, one of four receptor subtypes for PGE 2. After the second trimester, high concentration of prostaglandin E 2 (PGE 2) causes the DA to dilate through the remainder of the fetal period. In addition, fetal molecular remodeling that is suitable for postnatal muscle contraction has been observed in the DA. Anatomical closure of the DA is associated with the formation of intimal thickening, which is characterized by deposition of extracellular matrix in the subendothelial region, sparse elastic fiber formation, and migration of medial smooth muscle cells into the subendothelial space. Complete closure of the DA involves both functional closure, induced by muscle contraction, and anatomical closure, achieved through morphological and molecular remodeling. In certain DA-dependent congenital heart diseases, however, patient survival depends on maintaining DA patency. Persistent DA patency usually has life-threatening consequences. The ductus arteriosus (DA), a fetal arterial connection between the pulmonary arteries and aorta, normally closes after birth.

Heart pro ductus arteriosus