Failure of postnatal ductus arteriosus closure in prostaglandin transporter-deficient mice

Background-:Prostaglandin E₂ (PGE₂) plays a major role both in maintaining patency of the fetal ductus arteriosus and in closure of the ductus arteriosus after birth. The rate-limiting step in PGE₂ signal termination is PGE₂ uptake by the transporter PGT. Methods and Results-: To determine the role of PGT in ductus arteriosus closure, we used a gene-targeting strategy to produce mice in which PGT exon 1 was flanked by loxP sites. Successful targeting was obtained because neither mice hypomorphic at the PGT allele (PGT Neo/Neo) nor global PGT knockout mice (PGT^-/-) exhibited PGT protein expression; moreover, embryonic fibroblasts isolated from targeted mice failed to exhibit carrier-mediated PGE₂ uptake. Although born in a normal mendelian ratio, no PGT^-/- mice survived past postnatal day 1, and no PGT^-/- Neo/Neo mice survived past postnatal day 2. Necropsy revealed patent ductus arteriosus with normal intimal thickening but dilated cardiac chambers. Both PGT Neo/Neo and PGT mice could be rescued through the postnatal period by giving the mother indomethacin before birth. Rescued mice grew normally and had no abnormalities by gross and microscopic postmortem analyses. In accordance with the known role of PGT in metabolizing PGE₂, rescued adult PGT^-/- mice had lower plasma PGE₂ metabolite levels and higher urinary PGE₂ excretion rates than wild-type mice. CONCLUSION-: PGT plays a critical role in closure of the ductus arteriosus after birth by ensuring a reduction in local and/or circulating PGE₂ concentrations.