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

• Published in: The Journal of experimental medicine Vol. 193; no. 9; pp. 1005 - 1014
• Main Authors: 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, Rafii, S
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 07-05-2001
• Subjects: Adenoviridae; Angiopoietin-1; Animals; Bone Marrow Cells; Endothelial Growth Factors - administration & dosage; Endothelial Growth Factors - blood; Endothelial Growth Factors - metabolism; Endothelial Growth Factors - physiology; Female; Genetic Vectors; Hematopoiesis - physiology; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells - physiology; Leukocytes - physiology; Lymphokines - administration & dosage; Lymphokines - blood; Lymphokines - metabolism; Lymphokines - physiology; Male; Membrane Glycoproteins - administration & dosage; Membrane Glycoproteins - blood; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - physiology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, SCID; Neoplasm Proteins - metabolism; Original; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases - metabolism; Receptors, Growth Factor - metabolism; Receptors, Vascular Endothelial Growth Factor; Signal Transduction - physiology; Spleen - cytology; Time Factors; vascular endothelial growth factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
• ISSN: 0022-1007; 1540-9538; 1892-1007
• DOI: 10.1084/jem.193.9.1005

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.