title: Chronic in utero cyclooxygenase inhibition alters PGE2-regulated ductus arteriosus contractile pathways and prevents postnatal closure.
abstract: Although prostaglandin E2 (PGE2) vasodilates the ductus arteriosus, tocolysis with cyclooxygenase (COX) inhibitors delays postnatal ductus arteriosus closure. We used fetal mice and sheep to determine whether PGE2 has a role in the development of ductus contractility that is distinct from its function as a vasodilator. Prolonged exposure of fetal ductus to PGE2 in vitro increased the expression of CaL- and K+-channel genes (CaLalpha1c, CaLbeta2, Kir6.1, and Kv1.5, which regulate oxygen-induced constriction) without affecting the genes that regulate Rho-kinase-mediated calcium sensitization. Conversely, chronic exposure to COX inhibitors in utero decreased expression of CaL- and K+-channel genes, without affecting Rho-kinase-associated genes. Chronic COX inhibition in utero decreased the ductus' in vitro contractile response to stimuli that use CaL- and K+-channels (like O2 and K+), whereas the response to stimuli that act through Rho-kinase-mediated pathways (like U46619) was not significantly affected. Phosphodiesterase expression, which decreases the ductus' sensitivity to cAMP- or cGMP-dependent vasodilators, was increased by PGE2 exposure and decreased by COX inhibition, respectively. These studies identify potential downstream effectors of a PGE2-mediated, developmental program, regulating oxygen-induced ductus closure. Alterations in these effectors may explain the increased risk of patent ductus arteriosus (PDA) after in utero COX inhibition.
authors.affiliation: Department of Pediatrics, Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Reese
authors.forename: Nahid
authors.initials: N
authors.lastname: Waleh
authors.forename: Stanley D
authors.initials: SD
authors.lastname: Poole
authors.forename: Naoko
authors.initials: N
authors.lastname: Brown
authors.forename: Christine
authors.initials: C
authors.lastname: Roman
authors.forename: Ronald I
authors.initials: RI
authors.lastname: Clyman
mesh_terms: D000818:Animals; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D004373:Ductus Arteriosus / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D010100:Oxygen / Q000378:metabolism; D011247:Pregnancy; D012756:Sheep; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D010100:Oxygen