title: Oxygen-sensitive Kv channel gene transfer confers oxygen responsiveness to preterm rabbit and remodeled human ductus arteriosus: implications for infants with patent ductus arteriosus.
abstract: BACKGROUND
  Oxygen (O2)-sensitive K+ channels mediate acute O2 sensing in many tissues. At birth, initial functional closure of the ductus arteriosus (DA) results from O2-induced vasoconstriction. This mechanism often fails in premature infants, resulting in persistent DA, a common form of congenital heart disease. We hypothesized that the basis for impaired O2 constriction in preterm DA is reduced expression and function of O2-sensitive, voltage-gated (Kv) channels.
  
  
  RESULTS
  Preterm rabbit DA rings have reduced O2 constriction (even after inhibition of prostaglandin and nitric oxide synthases), and preterm DA smooth muscle cells (DASMCs) display reduced O2-sensitive K+ current. This is associated with decreased mRNA and protein expression of certain O2-sensitive Kv channels (Kv1.5 and Kv2.1) but equivalent expression of the L-type calcium channel. Transmural Kv1.5 or Kv2.1 gene transfer "rescues" the developmental deficiency, conferring O2 responsiveness to preterm rabbit DAs. Targeted SMC Kv1.5 gene transfer also enhances O2 constriction in human DAs.
  
  
  CONCLUSIONS
  These data demonstrate a central role for developmentally regulated DASMC O2-sensitive Kv channels in the functional closure of the DA. Modulation of Kv channels may have therapeutic potential in diseases associated with impaired O2 responsiveness, including persistent DA.
authors.affiliation: Vascular Biology Group, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thébaud
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
authors.forename: Xi-Chen
authors.initials: XC
authors.lastname: Wu
authors.forename: Rohit
authors.initials: R
authors.lastname: Moudgil
authors.forename: Michael
authors.initials: M
authors.lastname: Kuzyk
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Gwyneth
authors.initials: G
authors.lastname: Harry
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Alois
authors.initials: A
authors.lastname: Haromy
authors.forename: Ivan
authors.initials: I
authors.lastname: Rebeyka
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D004373:Ductus Arteriosus / Q000503:physiopathology*; D004374:Ductus Arteriosus, Patent / Q000209:etiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000032:analysis; D006801:Humans; D007231:Infant, Newborn; D051666:Kv1.5 Potassium Channel; D010100:Oxygen / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy; D047928:Premature Birth; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits; D051381:Rats; D051669:Shab Potassium Channels; D014161:Transduction, Genetic; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: C496981:KCNA5 protein, human; C496988:KCNB1 protein, human; C496983:Kcna5 protein, rat; D051666:Kv1.5 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D051669:Shab Potassium Channels; D049452:Green Fluorescent Proteins; D015761:4-Aminopyridine; D011188:Potassium; D010100:Oxygen