The ductus arteriosus is a specialized blood vessel containing highly differentiated and contractile vascular smooth muscle, derived largely from neural crest cells, that is essential for fetal life but typically closes after birth. Impaired development of the ductus arteriosus or disruption of signaling pathways that initiate postnatal closure, can result in persistent patency of the ductus arteriosus, the third most common congenital heart defect. We found that Tfap2, a transcription factor associated with patent ductus arteriosus in humans, was uniquely expressed in mouse ductal smooth muscle. Endothelin-1 and the hypoxia-induced transcription factor, Hif2 were also highly enriched in ductal smooth muscle at embryonic day 13.5 and were dependent on Tfap2 for their expression in this domain. Hif2 functioned as a negative regulator of Tfap2-induced transcription by disrupting protein–DNA interactions, suggesting a negative feedback loop regulating Tfap2 activity. Our data indicate that Tfap2, Et-1, and Hif2 act in a transcriptional network during ductal smooth muscle development and that disruption of this pathway may contribute to patent ductus arteriosus by affecting the development of smooth muscle within the ductus arteriosus.