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Original Article

^a Division of Hematology-Oncology, Critical Care Medicine and Genetic Medicine Program, Cornell University Medical College, New York, New York 10021
^b Division of Pulmonary, Critical Care Medicine and Genetic Medicine Program, Cornell University Medical College, New York, New York 10021
^c Sloan-Kettering Institute for Cancer Research, New York, New York 10021
^d Department of Pathology, Sapporo City General Hospital, Sapporo 060-8604, Japan
^e ImClone Systems Inc., New York, New York 10014
Cornell University Medical College, Division of Hematology-Oncology, 1300 York Ave., Rm. C-606, New York, NY 10021.212-746-8866212-746-2070

srafii{at}mail.med.cornell.edu

Tyrosine kinase receptors for angiogenic factors vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) are expressed not only by endothelial cells but also by subsets of hematopoietic stem cells (HSCs). To further define their role in the regulation of postnatal hematopoiesis and vasculogenesis, VEGF and Ang-1 plasma levels were elevated by injecting recombinant protein or adenoviral vectors expressing soluble VEGF₁₆₅, matrix-bound VEGF₁₈₉, or Ang-1 into mice. VEGF₁₆₅, but not VEGF₁₈₉, induced a rapid mobilization of HSCs and VEGF receptor (VEGFR)2⁺ circulating endothelial precursor cells (CEPs). In contrast, Ang-1 induced delayed mobilization of CEPs and HSCs. Combined sustained elevation of Ang-1 and VEGF₁₆₅ was associated with an induction of hematopoiesis and increased marrow cellularity followed by proliferation of capillaries and expansion of sinusoidal space. Concomitant to this vascular remodeling, there was a transient depletion of hematopoietic activity in the marrow, which was compensated by an increase in mobilization and recruitment of HSCs and CEPs to the spleen resulting in splenomegaly. Neutralizing monoclonal antibody to VEGFR2 completely inhibited VEGF₁₆₅, but not Ang-1–induced mobilization and splenomegaly. These data suggest that temporal and regional activation of VEGF/VEGFR2 and Ang-1/Tie-2 signaling pathways are critical for mobilization and recruitment of HSCs and CEPs and may play a role in the physiology of postnatal angiogenesis and hematopoiesis.

Key Words: vascular endothelial growth factor • angiopoietin-1 • angiogenesis • hematopoiesis • tyrosine kinase receptors

© 2001 The Rockefeller University Press

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This article has been cited by other articles:

• Kim, D. H., Xu, W., Kamel-Reid, S., Liu, X., Jung, C. W., Kim, S., Lipton, J. H. (2009). Clinical relevance of vascular endothelial growth factor (VEGFA) and VEGF receptor (VEGFR2) gene polymorphism on the treatment outcome following imatinib therapy. Ann Oncol 0: mdp452v1-mdp452 [Abstract] [Full Text]  

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