Granulocyte colony-stimulating factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils

FASEB J. 2005 Dec;19(14):2005-7. doi: 10.1096/fj.04-3496fje. Epub 2005 Oct 13.


The granulocyte colony-stimulating factor (G-CSF) promotes angiogenesis. However, the exact mechanism is not known. We demonstrate that vascular endothelial growth factor (VEGF) was released by Gr-1+CD11b- neutrophils but not Gr-1-CD11b+ monocytes prestimulated with G-CSF in vitro and in vivo. Similarly, in vivo, concomitant with an increase in neutrophil numbers in circulation, G-CSF augmented plasma VEGF level in vivo. Local G-CSF administration into ischemic tissue increased capillary density and provided a functional vasculature and contributed to neovascularization of ischemic tissue. Blockade of the VEGF pathway abrogated G-CSF-induced angiogenesis. On the other hand, as we had shown previously, VEGF can induce endothelial progenitor cell (EPC) mobilization. Here, we show that G-CSF also augmented the number of circulating VEGF receptor-2 (VEGFR2) EPCs as compared with untreated controls. Blocking the VEGF/VEGFR1, but to a much lesser extent, the VEGF/VEGFR2 pathway in G-CSF-treated animals delayed tissue revascularization in a hindlimb model. These data clearly show that G-CSF modulates angiogenesis by increasing myelomonocytic cells (VEGFR1+ neutrophils) and their release of VEGF. Our results indicated that administration of G-CSF into ischemic tissue provides a novel and safe therapeutic strategy to improve neovascularization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • CD11b Antigen / biosynthesis
  • Capillaries / pathology
  • Cells, Cultured
  • Collagen / chemistry
  • Drug Combinations
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism
  • Granulocyte Colony-Stimulating Factor / metabolism
  • Granulocyte Colony-Stimulating Factor / physiology*
  • Hematopoietic Stem Cells / cytology
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Ischemia / pathology
  • Laminin / chemistry
  • Leukocytes, Mononuclear / cytology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Statistical
  • Monocytes / cytology
  • Neovascularization, Pathologic
  • Neutrophils / metabolism
  • Proteoglycans / chemistry
  • Recombinant Proteins / chemistry
  • Stem Cells / cytology
  • Time Factors
  • Vascular Endothelial Growth Factor A / blood
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism


  • CD11b Antigen
  • Drug Combinations
  • Laminin
  • Proteoglycans
  • Recombinant Proteins
  • Vascular Endothelial Growth Factor A
  • matrigel
  • Granulocyte Colony-Stimulating Factor
  • Collagen
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor Receptor-2