title: Ecto-5'-nucleotidase, CD73, is an endothelium-derived hyperpolarizing factor synthase.
abstract: OBJECTIVE
  Adenosine dilates human coronary arteries by activating potassium channels in an endothelial cell-independent manner. Cell surface ecto-5'-nucleotidase (CD73) rapidly dephosphorylates extracellular adenosine 5'-monophosphate to adenosine. We tested the hypothesis that coronary vasodilation to adenine nucleotides is mediated by an endothelial CD73-dependent, extracellular production of adenosine that acts as an endothelium-derived hyperpolarizing factor.
  
  
  RESULTS
  Videomicroscopy showed that adenine nucleotides, but not inosine, potently dilated and hyperpolarized human coronary arteries independent of nitric oxide, prostacyclin, and classical endothelium-derived hyperpolarizing factors, whereas endothelial denudation, adenosine receptor antagonism, adenosine deaminase, or CD73 blockers reduced vasodilations. Liquid chromatography-electrospray ionization-mass spectrometry revealed adenosine accumulation in perfusates from arteries in the presence of adenosine 5'-diphosphate. CD73 was localized on the cell surface of endothelial cells, but not of vascular smooth muscle cells, and its deficiency suppressed vasodilation of mouse coronary arteries to adenine nucleotides and augmented vasodilation to adenosine. Adenosine dose-dependently dilated and hyperpolarized human coronary arteries to a similar extent as adenosine 5'-diphosphate.
  
  
  CONCLUSIONS
  Coronary vasodilation to adenine nucleotides is associated with endothelial CD73-dependent production of extracellular adenosine that acts as an endothelium-derived hyperpolarizing factor by relaxing and hyperpolarizing underlying vascular smooth muscle cells via activating adenosine receptors. Thus, CD73 is a novel endothelium-derived hyperpolarizing factor synthase in human and mouse coronary arteries.
authors.affiliation: Department of Medicine and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Ohta
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Toyama
authors.forename: David D
authors.initials: DD
authors.lastname: Gutterman
authors.forename: William B
authors.initials: WB
authors.lastname: Campbell
authors.forename: Vincent
authors.initials: V
authors.lastname: Lemaître
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Teraoka
authors.forename: Hiroto
authors.initials: H
authors.lastname: Miura
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000227:Adenine Nucleotides / Q000378:metabolism / Q000494:pharmacology*; D000241:Adenosine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000378:metabolism; D000818:Animals; D001685:Biological Factors / Q000378:metabolism*; D002853:Chromatography, Liquid; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007292:Inosine Nucleotides / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D018715:Microscopy, Video; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000227:Adenine Nucleotides; D001685:Biological Factors; D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D007292:Inosine Nucleotides; D058915:Purinergic P1 Receptor Antagonists; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D015720:5'-Nucleotidase; C548241:NT5E protein, human; C548242:Nt5e protein, mouse; D000243:Adenosine Deaminase; D000241:Adenosine