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Blood, 15 July 2005, Vol. 106, No. 2, pp. 505-513. Prepublished online as a Blood First Edition Paper on April 7, 2005; DOI 10.1182/blood-2004-11-4269. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-11-4269v1 106/2/505    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kopp, H.-G. Articles by Rafii, S. Search for Related Content PubMed PubMed Citation Articles by Kopp, H.-G. Articles by Rafii, S. Related Collections Hematopoiesis and Stem Cells Hemostasis, Thrombosis, and Vascular Biology Neoplasia Signal Transduction Gene Expression Free Research Articles Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Tie2 activation contributes to hemangiogenic regeneration after myelosuppression Hans-Georg Kopp, Scott T. Avecilla, Andrea T. Hooper, Sergey V. Shmelkov, Carlos A. Ramos, Fan Zhang, and Shahin Rafii From the Department of Genetic Medicine and the Division of Hematology-Oncology, Department of Medicine, Weill Medical College of Cornell University; and the Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Chemotherapy- or radiation-induced myelosuppression results in apoptosis of cycling hematopoietic cells and induces regression of bone marrow (BM) sinusoidal vessels. Moreover, timely regeneration of BM neovessels is essential for reconstitution of hematopoiesis. However, the identity of angiogenic factors that support reconstitution of BM's vasculature is unknown. Here, we demonstrate that angiopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains-2 (Tie2) signaling contributes to the assembly and remodeling of BM neovessels after myelosuppression. Using transgenic mice where the Tie2 promoter drives the reporter LacZ gene (Tie2-LacZ), we demonstrate that at steady state, there was minimal expression of Tie2 in the BM vasculature. However, after 5-fluorouracil (5-FU) treatment, there was a rapid increase in plasma vascular endothelial growth factor A (VEGF-A) levels and expansion of Tie2-positive neovessels. Inhibition of Tie2 resulted in impaired neoangiogenesis, leading to a delay in hematopoietic recovery. Conversely, angiopoietin-1 (Ang-1) stimulated hematopoiesis both in wild-type and thrombopoietin-deficient mice. In addition, Ang-1 shortened the duration of chemotherapy-induced neutropenia in wild-type mice. Exogenous VEGF-A and Ang-1 stimulated Tie2 expression in the BM vasculature. These data suggest that VEGF-A–induced up-regulation of Tie2 expression on the regenerating vasculature after BM suppression supports the assembly of sinusoidal endothelial cells, thereby promoting reconstitution of hematopoiesis. Angiopoietins may be clinically useful to accelerate hemangiogenic recovery after myelosuppression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Revascularization and hematopoietic recovery following myelosuppression are "Tied" together Laurie A. Milner Blood 2005 106: 391-392. [Full Text] [PDF] This article has been cited by other articles: A. B. Salter, S. K. Meadows, G. G. Muramoto, H. Himburg, P. Doan, P. Daher, L. Russell, B. Chen, N. J. Chao, and J. P. Chute Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo Blood, February 26, 2009; 113(9): 2104 - 2107. [Abstract] [Full Text] [PDF] W. B. Slayton, X.-M. Li, J. Butler, S. M. Guthrie, M. L. Jorgensen, J. R. Wingard, and E. W. Scott The Role of the Donor in the Repair of the Marrow Vascular Niche Following Hematopoietic Stem Cell Transplant Stem Cells, November 1, 2007; 25(11): 2945 - 2955. [Abstract] [Full Text] [PDF] R. Riccioni, D. Diverio, G. Mariani, S. Buffolino, V. Riti, E. Saulle, E. Petrucci, M. Cedrone, F. Lo-Coco, R. Foa, et al. Expression of Tie-2 and Other Receptors for Endothelial Growth Factors in Acute Myeloid Leukemias Is Associated with Monocytic Features of Leukemic Blasts Stem Cells, August 1, 2007; 25(8): 1862 - 1871. [Abstract] [Full Text] [PDF] J. P. Chute, G. G. Muramoto, A. B. Salter, S. K. Meadows, D. W. Rickman, B. Chen, H. A. Himburg, and N. J. Chao Transplantation of vascular endothelial cells mediates the hematopoietic recovery and survival of lethally irradiated mice Blood, March 15, 2007; 109(6): 2365 - 2372. [Abstract] [Full Text] [PDF] A. Goel, A. Dispenzieri, S. M. Geyer, S. Greiner, K.-W. Peng, and S. J. Russell Synergistic activity of the proteasome inhibitor PS-341 with non-myeloablative 153-Sm-EDTMP skeletally targeted radiotherapy in an orthotopic model of multiple myeloma Blood, May 15, 2006; 107(10): 4063 - 4070. [Abstract] [Full Text] [PDF] M. L. Cher, D. A. Towler, S. Rafii, D. Rowley, H. J. Donahue, E. Keller, M. Herlyn, E. A. Cho, and L. W.K. Chung Cancer Interaction with the Bone Microenvironment: A Workshop of the National Institutes of Health Tumor Microenvironment Study Section Am. J. Pathol., May 1, 2006; 168(5): 1405 - 1412. [Full Text] [PDF] H.-G. Kopp, S. T. Avecilla, A. T. Hooper, and S. Rafii The Bone Marrow Vascular Niche: Home of HSC Differentiation and Mobilization Physiology, October 1, 2005; 20(5): 349 - 356. [Abstract] [Full Text] [PDF]

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