Increases in oxygen tension stimulate expression of ICAM-1 and VCAM-1 on human endothelial cells.
Leukocyte infiltration plays a major role in ischemia-associated organ dysfunction and damage. A crucial step for extravasation of white blood cells is binding of leukocyte beta-integrins to endothelial adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1). To test for direct effects of oxygen on this process we studied ICAM-1 and VCAM-1 expression in human dermal microvascular and umbilical vein endothelial cells (EC) exposed to different oxygen tensions in the absence or presence of tumor necrosis factor-alpha (TNF-alpha). Hypoxia (95% N2-5% CO2) resulted in a downregulation of basal but not TNF-alpha-induced expression of ICAM-1 and VCAM-1. Subsequent rises in oxygen (21, 40, or 95% O2) led to marked increase of ICAM-1 and VCAM-1 cell surface and mRNA expression in both EC types, which after 16 h amounted to about one-third to one-half of maximal TNF-alpha-induced expression. This increase was greatest after 0.5-h hypoxia and was blunted with prolonged hypoxic preincubation. Exposure of cells preincubated under "normoxic" (21% O2) conditions to hyperoxia (40 or 95% O2) also enhanced expression of both adhesion molecules, but the increase was lower than in cells preexposed to hypoxia. The nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) enhanced ICAM-1 and VCAM-1 expression under basal and hypoxic conditions, but in the presence of L-NAME, levels in reoxygenated cells were not higher than basal levels. Moreover, the oxygen-induced rise could be mimicked by addition of H2O2 to normoxic cells, and the oxygen-induced expression of VCAM-1 but not of ICAM-1 was inhibited by addition of the free radical scavengers superoxide dismutase, N-acetyl-L-cysteine, and pyrrolidinedithiocarbamate. These data indicate that an increase in oxygen availability stimulates ICAM-1 and VCAM-1 expression on micro- and macrovascular EC, which may contribute to adhesion and transmigration of different leukocyte populations in ischemia-reperfusion injuries.
Willam
C
C
Department of Nephrology and Medical Intensive Care, Charité, Campus Virchow-Klinikum, 13353 Berlin, Germany.
Schindler
R
R
Frei
U
U
Eckardt
K U
KU
D002478:Cells, Cultured; D003470:Culture Media / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
D003470:Culture Media; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D006861:Hydrogen Peroxide; D010100:Oxygen; D019331:NG-Nitroarginine Methyl Ester