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Am J Physiol Heart Circ Physiol (January 21, 2005). doi:10.1152/ajpheart.00986.2004
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Submitted on September 24, 2004
Accepted on January 17, 2005

Critical Role of Endothelial Cell Activation in Hypoxia-Induced Vaso-occlusion in Transgenic Sickle Mice

John D Belcher1*, Hemchandra Mahaseth2, Thomas E Welch2, Asa E Vilback2, Khalid M Sonbol2, Venkatasubramaniam S Kalambur3, Paul R Bowlin2, John C Bischof3, Robert P Hebbel1, and Gregory M Vercellotti1

1 Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA; Vascular Biology Center, University of Minnesota, Minneapolis, MN, USA
2 Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA
3 Department of Mechanical Engineering, University of Minnesota, Minneapolis, MN, USA

* To whom correspondence should be addressed. E-mail: belcher{at}umn.edu.

Activation of vascular endothelium plays an essential role in vaso-occlusion in sickle cell disease. Anti-inflammatory agents, dexamethasone and adhesion molecule blocking antibodies, were used to inhibit endothelial cell activation and hypoxia-induced vaso-occlusion. Transgenic sickle mice, expressing human {alpha}, {beta}S and {beta}S-Antilles globins, had an activated vascular endothelium in their liver, lungs, and skin, exhibited by increased activation of NF-{kappa}B compared to normal mice. NF-{kappa}B activation increased further in the liver and skin after exposing sickle mice to hypoxia. Sickle mice had decreases in red blood cell (RBC) velocities and developed vaso-occlusions in subcutaneous venules in response to hypoxia. Dexamethasone pre-treatment prevented decreases in RBC velocities and inhibited vaso-occlusions and leukocyte-endothelium interactions in venules after hypoxia. Dexamethasone treatment inhibited NF-{kappa}B, VCAM-1 and ICAM-1 expression in the liver, lungs and skin of sickle mice after hypoxia-reoxygenation. VCAM-1 or ICAM-1 blockade with monoclonal antibodies (MAb)mimicked dexamethasone by inhibiting vaso-occlusion and leukocyte adhesion in sickle mice, demonstrating that endothelial cell activation and VCAM-1 and ICAM-1 expression are necessary for hypoxia-induced vaso-occlusion in sickle mice. VCAM-1, ICAM-1 and vaso-occlusion increased significantly three days after dexamethasone discontinuation, possibly explaining rebounds in vaso-occlusive crises observed after withdrawal of glucocorticosteroids in sickle patients. We conclude that anti-inflammatory treatments that inhibit endothelial cell activation and adhesion molecule expression can inhibit vaso-occlusion in sickle cell disease. Rebounds in vaso-occlusive crises after dexamethasone withdrawal are caused by rebounds in endothelial cell activation.




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