Discerning the Role of Prostaglandins in Ductus Arteriosus Remodeling

The ductus arteriosus (DA) is a fetal pulmonary bypass shunt that constricts and permanently remodels during the transition from fetal to adult circulation. Prostaglandin E2 (PGE2) is potent mediator of numerous physiological responses both in homeostasis and disease state. PGE2 play a vital role in DA maturation and closure, although the exact molecular role is unclear. We attempt to discern the nature of PGE2 involvement in DA maturation and closure. Here we generate a conditional null allele of the prostaglandin E receptor 4 (EP4), which has been previously shown to be responsible for PGE2 signaling in the DA. Utilizing various tissue specific Cre recombinase transgenes, we have shown that EP4 expression on the neural crest derived smooth muscle cells of the DA is critical for proper DA closure. We have also shown that endothelial expression of the PGE2 vasodilatory receptors (EP4 and EP2) is non-essential for DA closure or vascular development. Genome wide expression profiling of the wildtype DA and EP4 deficient DA were used to assess the transcriptional consequences of PGE2/EP4 signaling in the DA. Differentially expressed genes in the wildtype DA indicate that EP4 receptor expression leads to the up-regulation of numerous cytoskeletal genes. The relative minor increase (