title: Endothelial cell NADPH oxidase mediates the cerebral microvascular dysfunction in sickle cell transgenic mice.
abstract: Although blood cell-endothelial cell adhesion and oxidative stress have been implicated in the pathogenesis of sickle cell disease (SCD), the nature of the linkage between these vascular responses in SCD remains unclear. The objective of this study was to determine whether superoxide derived from endothelial cell-associated NADPH oxidase mediates the leukocyte-endothelial (L/E) and platelet-endothelial cell (P/E) adhesion that is observed in the cerebral microvasculature of sickle cell transgenic (betaS) mice. Intravital fluorescence microscopy was used to monitor L/E and P/E adhesion in brain postcapillary venules of wild-type (WT), SOD1 transgenic (SOD1-TgN), and gp91phox (NADPH oxidase)-deficient mice that were transplanted with bone marrow from betaS mice. Hypoxia/reoxygenation (H/R) yielded intense P/E and L/E adhesion responses in cerebral venules of betaS/WT chimeras that were significantly attenuated in both betaS/SOD1-TgN, and betaS/gp91phox-/- chimeras. Pretreatment of betaS/WT chimeras with the iron-chelator desferroxamine blunted the blood cell-endothelial cell adhesion responses to H/R, whereas pretreatment with the xanthine oxidase inhibitor allopurinol had no effect. These findings suggest that superoxide derived from endothelial cell NADPH-oxidase and catalytically active iron contribute to the proinflammatory and prothrombogenic responses associated with sickle cell disease.
authors.affiliation: Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana 71130-3932, USA.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Wood
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hebbel
authors.forename: D Neil
authors.initials: DN
authors.lastname: Granger
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000755:Anemia, Sickle Cell / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D016026:Bone Marrow Transplantation; D001921:Brain / Q000098:blood supply*; D003676:Deferoxamine / Q000494:pharmacology; D042783:Endothelial Cells / Q000201:enzymology*; D015870:Gene Expression; D018056:Hemorheology; D006801:Humans; D007249:Inflammation; D007501:Iron / Q000502:physiology; D007502:Iron Chelating Agents / Q000494:pharmacology; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008833:Microcirculation / Q000503:physiopathology*; D008856:Microscopy, Fluorescence; D019255:NADPH Oxidases / Q000502:physiology*; D010973:Platelet Adhesiveness; D013482:Superoxide Dismutase / Q000235:genetics; D013927:Thrombosis; D018183:Transplantation Chimera; D014699:Venules / Q000503:physiopathology; D014969:Xanthine Oxidase / Q000502:physiology
chemical_list: D007502:Iron Chelating Agents; D000493:Allopurinol; D007501:Iron; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D003676:Deferoxamine