Publication Type	Academic Article
Authors	Hattori K, Dias S, Heissig B, Hackett N, Lyden D, Tateno M, Hicklin D, Zhu Z, Witte L, Crystal R, Moore M, Rafii S
Journal	J Exp Med
Volume	193
Issue	9
Pagination	1005-14
Date Published	05/07/2001
ISSN	0022-1007
Keywords	Endothelial Growth Factors, Hematopoiesis, Hematopoietic Stem Cells, Lymphokines, Membrane Glycoproteins, Proto-Oncogene Proteins, Signal Transduction
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 VEGF(165), matrix-bound VEGF(189), or Ang-1 into mice. VEGF(165), but not VEGF(189), 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 VEGF(165) 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 VEGF(165), 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.
DOI	10.1084/jem.193.9.1005
PubMed ID	11342585
PubMed Central ID	PMC2193424