Granulocyte/macrophage colony-stimulating factor influences angiogenesis by regulating the coordinated expression of VEGF and the Ang/Tie system

PLoS One. 2014 Mar 21;9(3):e92691. doi: 10.1371/journal.pone.0092691. eCollection 2014.

Abstract

Granulocyte/macrophage colony-stimulating factor (GM-CSF) can accelerate wound healing by promoting angiogenesis. The biological effects of GM-CSF in angiogenesis and the corresponding underlying molecular mechanisms, including in the early stages of primitive endothelial tubule formation and the later stages of new vessel maturation, have only been partially clarified. This study aimed to investigate the effects of GM-CSF on angiogenesis and its regulatory mechanisms. Employing a self-controlled model (Sprague-Dawley rats with deep partial-thickness burn wounds), we determined that GM-CSF can increase VEGF expression and decrease the expression ratio of Ang-1/Ang-2 and the phosphorylation of Tie-2 in the early stages of the wound healing process, which promotes the degradation of the basement membrane and the proliferation of endothelial cells. At later stages of wound healing, GM-CSF can increase the expression ratio of Ang-1/Ang-2 and the phosphorylation of Tie-2 and maintain a high VEGF expression level. Consequently, pericyte coverages were higher, and the basement membrane became more integrated in new blood vessels, which enhanced the barrier function of blood vessels. In summary, we report here that increased angiogenesis is associated with GM-CSF treatment, and we indicate that VEGF and the Ang/Tie system may act as angiogenic mediators of the healing effect of GM-CSF on burn wounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Burns / genetics
  • Burns / metabolism
  • Cell Proliferation / drug effects
  • Endothelial Cells / metabolism
  • Gene Expression Regulation / drug effects*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Neovascularization, Physiologic / drug effects*
  • Neovascularization, Physiologic / genetics*
  • Pericytes / drug effects
  • Pericytes / metabolism
  • Phosphorylation
  • Rats
  • Receptors, TIE / genetics*
  • Receptors, TIE / metabolism
  • Ribonuclease, Pancreatic / genetics*
  • Ribonuclease, Pancreatic / metabolism
  • Vascular Endothelial Growth Factor A / genetics*
  • Wound Healing / drug effects
  • Wound Healing / genetics

Substances

  • Vascular Endothelial Growth Factor A
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Receptors, TIE
  • angiogenin
  • Ribonuclease, Pancreatic
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9

Grant support

The research was funded by the National Natural Science Foundation (81272153). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.