Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells.
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.
Hattori
K
K
Division of Hematology-Oncology, Critical Care Medicine and Genetic Medicine Program, Cornell University Medical College, New York, New York 10021, USA.
Dias
S
S
Heissig
B
B
Hackett
N R
NR
Lyden
D
D
Tateno
M
M
Hicklin
D J
DJ
Zhu
Z
Z
Witte
L
L
Crystal
R G
RG
Moore
M A
MA
Rafii
S
S
D000256:Adenoviridae; D042683:Angiopoietin-1; D000818:Animals; D001854:Bone Marrow Cells; D016228:Endothelial Growth Factors / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005822:Genetic Vectors; D006410:Hematopoiesis / Q000502:physiology*; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007962:Leukocytes / Q000502:physiology; D008222:Lymphokines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction / Q000502:physiology*; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D016228:Endothelial Growth Factors; D008222:Lymphokines; C105373:MEN1 protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor