A novel role for PGE₂-EP₄ in the developmental programming of the mouse ductus arteriosus: consequences for vessel...

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 E₂ (PGE₂) receptor EP₄. However, in humans and mice, disrupted PGE₂-EP₄ signaling in utero causes unexpected patency of the DA (PDA) after birth, suggesting another role for EP₄ during development. We used EP₄-knockout (KO) mice and acute versus chronic pharmacological approaches to investigate EP₄ signaling in DA development and function. Expression analyses identified EP₄ as the primary EP receptor in the DA from midgestation to term; inhibitor studies verified EP₄ as the primary dilator during this period. Chronic antagonism recapitulated the EP₄ KO phenotype and revealed a narrow developmental window when EP₄ stimulation is required for postnatal DA closure. Myography studies indicate that despite reduced contractile properties, the EP₄ KO DA maintains an intact oxygen response. In newborns, hyperoxia constricted the EP₄ KO DA but survival was not improved, and permanent remodeling was disrupted. Vasomotion and increased nitric oxide (NO) sensitivity in the EP₄ KO DA suggest incomplete DA development. Analysis of DA maturity markers confirmed a partially immature EP₄ KO DA phenotype. Together, our data suggest that EP₄ signaling in late gestation plays a key developmental role in establishing a functional term DA. When disrupted in EP₄ 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 EP₄ 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 EP₄-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.