AJP - Heart Ad Instruments
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
 QUICK SEARCH:   [advanced]


     


Am J Physiol Heart Circ Physiol (January 21, 2005). doi:10.1152/ajpheart.00986.2004
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
288/6/H2715    most recent
00986.2004v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Belcher, J. D
Right arrow Articles by Vercellotti, G. M
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Belcher, J. D
Right arrow Articles by Vercellotti, G. M
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.




This article has been cited by other articles:


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
J. D. Beckman, J. D. Belcher, J. V. Vineyard, C. Chen, J. Nguyen, M. O. Nwaneri, M. G. O'Sullivan, E. Gulbahce, R. P. Hebbel, and G. M. Vercellotti
Inhaled carbon monoxide reduces leukocytosis in a murine model of sickle cell disease
Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1243 - H1253.
[Abstract] [Full Text] [PDF]


Home page
JAMAHome page
G. J. Kato and M. T. Gladwin
Evolution of Novel Small-Molecule Therapeutics Targeting Sickle Cell Vasculopathy
JAMA, December 10, 2008; 300(22): 2638 - 2646.
[Abstract] [Full Text] [PDF]


Home page
NEJMHome page
M. T. Gladwin and E. Vichinsky
Pulmonary Complications of Sickle Cell Disease
N. Engl. J. Med., November 20, 2008; 359(21): 2254 - 2265.
[Full Text] [PDF]


Home page
BloodHome page
J. Chang, P. A. Shi, E. Y. Chiang, and P. S. Frenette
Intravenous immunoglobulins reverse acute vaso-occlusive crises in sickle cell mice through rapid inhibition of neutrophil adhesion
Blood, January 15, 2008; 111(2): 915 - 923.
[Abstract] [Full Text] [PDF]


Home page
BloodHome page
C. R. Morris, J. H. Suh, W. Hagar, S. Larkin, D. A. Bland, M. H. Steinberg, E. P. Vichinsky, M. Shigenaga, B. Ames, F. A. Kuypers, et al.
Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease
Blood, January 1, 2008; 111(1): 402 - 410.
[Abstract] [Full Text] [PDF]


Home page
J. Appl. Physiol.Home page
G. Monchanin, L. D. Serpero, P. Connes, J. Tripette, D. Wouassi, L. Bezin, A. Francina, J. Ngongang, M. de la Pena, R. Massarelli, et al.
Effects of progressive and maximal exercise on plasma levels of adhesion molecules in athletes with sickle cell trait with or without {alpha}-thalassemia
J Appl Physiol, January 1, 2007; 102(1): 169 - 173.
[Abstract] [Full Text] [PDF]


Home page
ASH Education BookHome page
M. J. Telen
Role of Adhesion Molecules and Vascular Endothelium in the Pathogenesis of Sickle Cell Disease
Hematology, January 1, 2007; 2007(1): 84 - 90.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
K. Inoue, M. Kobayashi, K. Yano, M. Miura, A. Izumi, C. Mataki, T. Doi, T. Hamakubo, P. C. Reid, D. A. Hume, et al.
Histone Deacetylase Inhibitor Reduces Monocyte Adhesion to Endothelium Through the Suppression of Vascular Cell Adhesion Molecule-1 Expression
Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2652 - 2659.
[Abstract] [Full Text] [PDF]




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Visit Other APS Journals Online
Copyright © 1977 by the American Physiological Society.