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

Abstract

The ductus arteriosus (DA) is a vascular shunt which allows oxygenated blood to bypass the developing lungs in utero. Fetal DA patency requires vasodilatory signaling via the prostaglandin (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 pharmacologic approaches to investigate EP4 signaling in DA development and function. Expression analyses identified EP4 as the primary EP receptor in the DA from mid-gestation 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 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.

Ductus Arteriosus in Fetal and Perinatal Life

“…Fetal DA patency is predominantly maintained through prostaglandin E2 (PGE2) activation, facilitated by the EP4 receptor, inducing DA dilation via the activation of the cAMP/PKA signaling pathway [17].…”

“…The complex transition of fetal circulation to postnatal hemodynamic status is a result of a multilevel interplay among biochemical, mechanical, and hormonal factors that are still not fully elucidated and, thus, are currently under investigation [16,17,[35][36][37].…”

Genetic Foundation of Prostaglandin Metabolism Influences Patent Ductus Arteriosus Closure in Extremely Low Birth Weight Infants

“…10 EP 4 has been described as the primary EP receptor in the DA as well as playing a critical role as a regulator of ductal development and maturity. 4 11 In fetal life, PG signaling via EP 4 leads to specific anatomic and molecular remodeling that allows for postnatal constriction via intimal thickening (deposition of extracellular matrix in subendothelial region), sparse elastic fiber formation, and migration of smooth muscle cells in the subendothelial space. 12 EP 4 knockout mice had patent DA phenotype, which was thought to be from impaired contractile potential, altered signaling, and vessel immaturity.…”

“…12 EP 4 knockout mice had patent DA phenotype, which was thought to be from impaired contractile potential, altered signaling, and vessel immaturity. 11 PGE 2 is degraded in the lungs by 15-hydroxyprostaglandin dehydrogenase (PGDH) to metabolites which are excreted in the urine (90%) and feces (10%). 9 Expression of PGDH increases dramatically late in gestation, particularly in the fetal lung.…”