Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells

Koichi Hattori, Sergio Dias, Beate Heissig, Neil R. Hackett, David Lyden, Masatoshi Tateno, Daniel J. Hicklin, Zhenping Zhu, Larry Witte, Ronald G. Crystal, Malcolm A.S. Moore, Shahin Rafii

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Abstract

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.

Original languageEnglish
Pages (from-to)1005-1014
Number of pages10
JournalJournal of Experimental Medicine
Volume193
Issue number9
DOIs
Publication statusPublished - 7 May 2001

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Keywords

  • Angiogenesis
  • Angiopoietin-1
  • Hematopoiesis
  • Tyrosine kinase receptors
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Hattori, K., Dias, S., Heissig, B., Hackett, N. R., Lyden, D., Tateno, M., Hicklin, D. J., Zhu, Z., Witte, L., Crystal, R. G., Moore, M. A. S., & Rafii, S. (2001). Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. Journal of Experimental Medicine, 193(9), 1005-1014. https://doi.org/10.1084/jem.193.9.1005