The ductus arteriosus (DA) begins to constrict immediately after birth and changes to a fibromuscular ligament over several months in humans.1 This functional DA closure is essential for adaptation to the postnatal atmospheric environment, and requires that DA smooth muscle cells (SMCs) are mature enough to contract rapidly after birth in response to increased oxygen tension and decreased circulating prostaglandin E2 (PGE2) concentrations.2 In addition to SMC maturation, histological studies in humans demonstrated that extensive structural remodeling occurs in the DA (Figure 1).3 The human DA tissues were obtained from term infants during congenital heart surgery. Cases 2 and 3 were considered to have physiologically developed DAs because they showed a DA closing tendency and required PGE1 administration. These DAs exhibited sparsely formed elastic fibers in the tunica media and prominent intimal thickening, which are DA-specific features. In contrast, case 1 was considered to have patent ductus arteriosus (PDA) and its DA had well-organized layered elastic fibers and poorly formed intimal thickening. Internal elastic lamina (IEL) interruption and subendothelial region widening, sparse elastic fiber formation, and prominent intimal thickening can be observed in the fetal period and are distinctive features of the DA. Once functional closure begins after birth, further extracellular matrix (ECM) remodeling occurs for eventual DA transformation into a ligament.2

From 1997 to date, 31 genetic mouse models of PDA have been reported.4, 5, 6, 7 Over 200 human single-gene syndromes that are associated with PDA have been identified, and some of the genes overlap between mouse models and humans.4 The availability of human PDA tissue is limited, and studies involving genetically modified mice have provided insights into molecular mechanisms of DA closure.

In this review, we focused on a molecular mechanism of ECM remodeling and regulation of cell migration/proliferation associated with postnatal anatomical closure of the DA.