Failure of postnatal ductus arteriosus closure in prostaglandin transporter-deficient mice.
BACKGROUND
Prostaglandin E(2) (PGE(2)) 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 PGE(2) signal termination is PGE(2) uptake by the transporter PGT.


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 PGE(2) 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 PGE(2), rescued adult PGT(-/-) mice had lower plasma PGE(2) metabolite levels and higher urinary PGE(2) excretion rates than wild-type mice.


CONCLUSIONS
PGT plays a critical role in closure of the ductus arteriosus after birth by ensuring a reduction in local and/or circulating PGE(2) concentrations.
Chang
Hee-Yoon
HY
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Locker
Joseph
J
Lu
Run
R
Schuster
Victor L
VL
D000818:Animals; D002317:Cardiovascular Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004373:Ductus Arteriosus / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D004374:Ductus Arteriosus, Patent / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D007213:Indomethacin / Q000627:therapeutic use; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D027361:Organic Anion Transporters / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D002317:Cardiovascular Agents; D027361:Organic Anion Transporters; D018078:Receptors, Prostaglandin E; C503527:Slco2a1 protein, mouse; D015232:Dinoprostone; D007213:Indomethacin