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 growt h factor (VEGF) and angiopoietin-1 (Ang-1) are expressed not only by endoth elial cells but also by subsets of hematopoietic stent cells (HSCs). To fur ther define their role in the regulation of postnatal hematopoiesis and vas culogenesis, VEGF and Ang-1 plasma levels were elevated by injecting recomb inant protein or adenoviral vectors expressing soluble VEGF(165), matrix-bo und 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 endoth elial precursor cells (CEPs). In contrast, Ang-1 induced delayed mobilizati on of CEPs and HSCs. Combined sustained elevation of Ang-1 and VEGF(165) wa s associated with an induct-ion of hematopoiesis and increased marrow cellu larity followed by proliferation of capillaries and expansion of sinusoidal space. Concomitant to this vascular remodeling, there was a transient depl etion of hematopoietic activity in the marrow, which was compensated by an increase in mobilization and recruitment of HSCs and CEPs to the spleen res ulting in splenomegaly. Neutralizing monoclonal antibody to VEGFR2 complete ly inhibited VEGF(165), but not Ang-1-induced mobilization and splenomegaly . These data suggest that temporal and regional activation of VEGF/VEGFR2 a nd Ang-1/Tie-2 signaling pathways are critical for mobilization and recruit ment of HSCs and CEPs and may play a role in the physiology of postnatal an giogenesis and hematopoiesis.