Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice

John D Belcher, Hemchandra Mahaseth, Thomas E. Welch, Asa E. Vilback, Khalid M. Sonbol, Venkatasubramaniam S. Kalambur, Paul R. Bowlin, John C Bischof, Robert P Hebbel, Gregory M Vercellotti

Research output: Contribution to journalArticle

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Abstract

Activation of vascular endothelium plays an essential role in vasoocclusion in sickle cell disease. The anti-inflammatory agents dexamethasone and adhesion molecule-blocking antibodies were used to inhibit endothelial cell activation and hypoxia-induced vasoocclusion. Transgenic sickle mice, expressing human α-, βS-, and β;S-Antilles-globins, had an activated vascular endothelium in their liver, lungs, and skin, as exhibited by increased activation of NF-κB compared with normal mice. NF-κB activation increased further in the liver and skin after sickle mice were exposed to hypoxia. Sickle mice had decreases in red blood cell (RBC) velocities and developed vasoocclusions in subcutaneous venules in response to hypoxia. Dexamethasone pretreatment prevented decreases in RBC velocities and inhibited vasoocclusions and leukocyte-endothelium interactions in venules after hypoxia. Dexamethasone treatment inhibited NF-κB, VCAM-1, and ICAM-1 expression in the liver, lungs, and skin of sickle mice after hypoxiareoxygenation. VCAM-1 or ICAM-1 blockade with monoclonal antibodies mimicked dexamethasone by inhibiting vasoocclusion and leukocyte adhesion in sickle mice, demonstrating that endothelial cell activation and VCAM-1 and ICAM-1 expression are necessary for hypoxia-induced vasoocclusion in sickle mice. VCAM-1, ICAM-1, and vasoocclusion increased significantly 3 days after dexamethasone discontinuation, possibly explaining rebounds in vasoocclusive 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 vasoocclusion in sickle cell disease. Rebounds in vasoocclusive crises after dexamethasone withdrawal are caused by rebounds in endothelial cell activation.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume288
Issue number6 57-6
DOIs
StatePublished - Jun 1 2005

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Dexamethasone
Transgenic Mice
Endothelial Cells
Vascular Cell Adhesion Molecule-1
Intercellular Adhesion Molecule-1
Venules
Vascular Endothelium
Sickle Cell Anemia
Skin
Liver
Leukocytes
Anti-Inflammatory Agents
Erythrocytes
Cell Hypoxia
Lung
Blocking Antibodies
Globins
Cell Adhesion Molecules
Endothelium
Hypoxia

Keywords

  • Dexamethasone
  • Intercellular adhesion molecule
  • Nuclear factor-κB
  • Sickle cell anemia
  • Vascular cell adhesion molecule

Cite this

Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice. / Belcher, John D; Mahaseth, Hemchandra; Welch, Thomas E.; Vilback, Asa E.; Sonbol, Khalid M.; Kalambur, Venkatasubramaniam S.; Bowlin, Paul R.; Bischof, John C; Hebbel, Robert P; Vercellotti, Gregory M.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 288, No. 6 57-6, 01.06.2005.

Research output: Contribution to journalArticle

Belcher, John D ; Mahaseth, Hemchandra ; Welch, Thomas E. ; Vilback, Asa E. ; Sonbol, Khalid M. ; Kalambur, Venkatasubramaniam S. ; Bowlin, Paul R. ; Bischof, John C ; Hebbel, Robert P ; Vercellotti, Gregory M. / Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice. In: American Journal of Physiology - Heart and Circulatory Physiology. 2005 ; Vol. 288, No. 6 57-6.
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AU - Kalambur, Venkatasubramaniam S.

AU - Bowlin, Paul R.

AU - Bischof, John C

AU - Hebbel, Robert P

AU - Vercellotti, Gregory M

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