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J. Biol. Chem., Vol. 278, Issue 24, 22006-22013, June 13, 2003

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Vascular Endothelial Growth Factor Receptor-2 Induces Survival of Hematopoietic Progenitor Cells^*

Bruno Larrivée   ¶, David R. Lane , Ingrid Pollet , Peggy L. Olive , R. Keith Humphries  || and Aly Karsan   **  

From the Departments of Medicine and ^**Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada and the Department of Medical Biophysics, the Department of Pathology and Laboratory Medicine, and ^||Terry Fox Laboratories, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada

Vascular endothelial growth factor (VEGF) and its receptors play an essential role in the formation and maintenance of the hematopoietic and vascular compartments. The VEGF receptor-2 (VEGFR-2) is expressed on a population of hematopoietic cells, although its role in hematopoiesis is still unclear. In this report, we have utilized a strategy to selectively activate VEGFR-2 and study its effects in primary bone marrow cells. We found that VEGFR-2 can maintain the hematopoietic progenitor population in mouse bone marrow cultured in the absence of exogenous cytokines. Maintenance of the hematopoietic progenitor population is due to increased cell survival with minimal effect on proliferation. Progenitor survival is mainly mediated by activation of the phosphatidylinositol 3'-kinase/Akt pathway. Although VEGFR-2 also activated Erk1/2 mitogen-activated protein kinase, it did not induce cell proliferation, and blockade of this pathway only partially decreased VEGFR-2-mediated survival of hematopoietic progenitors. Thus, the role of VEGFR-2 in hematopoiesis is likely to maintain survival of hematopoietic progenitors through the activation of antiapoptotic pathways.

Received for publication, December 1, 2002 , and in revised form, March 28, 2003.

^* This work was supported by the National Cancer Institute of Canada with funds from the Terry Fox Run and a grant-in-aid from the Heart and Stroke Foundation of British Columbia and the Yukon. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by a Doctoral Research Award from the Heart and Stroke Foundation of Canada.

A clinician-scientist of the Canadian Institutes of Health Research and a scholar of the Michael Smith Foundation for Health Research. To whom correspondence should be addressed: Dept. of Medical Biophysics, British Columbia Cancer Research Centre, 601 W. 10th Ave., Vancouver, British Columbia V5Z 1L3, Canada. E-mail: akarsan{at}bccancer.bc.ca.

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