title: Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors.
abstract: Limited oxygen delivery to tissues (hypoxia) is common in a variety of disease states. A number of parallels exist between hypoxia and acute inflammation, including the observation that both influence vascular permeability. As such, we compared the functional influence of activated polymorphonuclear leukocytes (PMN) on normoxic and posthypoxic endothelial cells. Initial studies indicated that activated PMN preferentially promote endothelial barrier function in posthypoxic endothelial cells (>60% increase over normoxia). Extension of these findings identified at least one soluble mediator as extracellular adenosine triphosphate (ATP). Subsequent studies revealed that ATP is coordinately hydrolyzed to adenosine at the endothelial cell surface by hypoxia-induced CD39 and CD73 (>20-and >12-fold increase in mRNA, respectively). Studies in vitro and in cd39-null mice identified these surface ecto-enzymes as critical control points for posthypoxia-associated protection of vascular permeability. Furthermore, insight gained through microarray analysis revealed that the adenosine A2B receptor (AdoRA2B) is selectively up-regulated by hypoxia (>5-fold increase in mRNA), and that AdoRA2B antagonists effectively neutralize ATP-mediated changes in posthypoxic endothelial permeability. Taken together, these results demonstrate transcription coordination of adenine nucleotide and nucleoside signaling at the vascular interface during hypoxia.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.forename: Juan C
authors.initials: JC
authors.lastname: Ibla
authors.forename: Glenn T
authors.initials: GT
authors.lastname: Furuta
authors.forename: Martin O
authors.initials: MO
authors.lastname: Leonard
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Keiichi
authors.initials: K
authors.lastname: Enjyoji
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism*; D000241:Adenosine / Q000502:physiology*; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000502:physiology; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D001081:Apyrase; D001483:Base Sequence; D015687:Cell Hypoxia / Q000502:physiology; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D008833:Microcirculation; D018375:Neutrophil Activation / Q000502:physiology; D009504:Neutrophils / Q000166:cytology / Q000502:physiology*; D010101:Oxygen Consumption; D011755:Pyrophosphatases / Q000378:metabolism*; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D000227:Adenine Nucleotides; D015703:Antigens, CD; D017931:DNA Primers; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1; D000251:Adenosine Triphosphatases; D011755:Pyrophosphatases; C092064:ectonucleotide pyrophosphohydrolase; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine