A novel role for PGE(2)-EP(4) in the developmental programming of the mouse ductus arteriosus: consequences for vessel maturation and function

The ductus arteriosus (DA) is a vascular shunt that allows oxygenated blood to bypass the developing lungs in utero. Fetal DA patency requires vasodilatory signaling via the prostaglandin E(2) (PGE(2)) receptor EP(4). However, in humans and mice, disrupted PGE(2)-EP(4) signaling in utero causes unexpected patency of the DA (PDA) after birth, suggesting another role for EP(4) during development. We used EP(4)-knockout (KO) mice and acute versus chronic pharmacological approaches to investigate EP(4) signaling in DA development and function. Expression analyses identified EP(4) as the primary EP receptor in the DA from midgestation to term; inhibitor studies verified EP(4) as the primary dilator during this period. Chronic antagonism recapitulated the EP(4) KO phenotype and revealed a narrow developmental window when EP(4) stimulation is required for postnatal DA closure. Myography studies indicate that despite reduced contractile properties, the EP(4) KO DA maintains an intact oxygen response. In newborns, hyperoxia constricted the EP(4) KO DA but survival was not improved, and permanent remodeling was disrupted. Vasomotion and increased nitric oxide (NO) sensitivity in the EP(4) KO DA suggest incomplete DA development. Analysis of DA maturity markers confirmed a partially immature EP(4) KO DA phenotype. Together, our data suggest that EP(4) signaling in late gestation plays a key developmental role in establishing a functional term DA. When disrupted in EP(4) KO mice, the postnatal DA exhibits signaling and contractile properties characteristic of an immature DA, including impairments in the first, muscular phase of DA closure, in addition to known abnormalities in the second permanent remodeling phase. NEW & NOTEWORTHY EP(4) is the primary EP receptor in the ductus arteriosus (DA) and is critical during late gestation for its development and eventual closure. The “paradoxical” patent DA (PDA) phenotype of EP(4)-knockout mice arises from a combination of impaired contractile potential, altered signaling properties, and a failure to remodel associated with an underdeveloped immature vessel. These findings provide new mechanistic insights into women who receive NSAIDs to treat preterm labor, whose infants have unexplained PDA.