Formononetin accelerates wound repair by the regulation of early growth response factor-1 transcription factor through the phosphorylation of the ERK and p38 MAPK pathways

Int Immunopharmacol. 2011 Jan;11(1):46-54. doi: 10.1016/j.intimp.2010.10.003. Epub 2010 Oct 16.


Formononetin, a phytoestrogen from the root of Astragalus membranaceus, is used as a blood enhancer and to improve blood microcirculation in complementary and alternative medicine. The present study investigated the influence of formononetin on the expression of early growth response factor-1 (Egr-1) and growth factors contributing to wound healing. Formononetin significantly increased growth factors such as transforming growth factor-beta 1 (TGF-β1), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) in human umbilical vein endothelial cells (HUVECs). Formononetin also increased the expression of Egr-1 transcription factor by 3.2- and 10.5-fold, compared with recombinant VEGF(125) in HUVECs. The formononetin-mediated 12%-43% increase induced endothelial cell proliferation and recovered the migration of wounded HUVECs. In an ex vivo angiogenesis assay, formononetin produced a larger capillary sprouting area than produced using recombinant VEGF(125). Cell proliferation and migration of HUVECs were also greater in the presence of formonectin than VEGF(125). Western blot analysis of scratch-wounded confluent HUVECs showed that formononetin induced the phosphorylation of extracellular signal-regulated kinase (ERK) and slightly inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK). The formononetin-mediated sustained activation of Egr-1 was suppressed by the ERK inhibitor PD98059 and the p38 inhibitor SB203580. PD98059 inhibited the formononetin-induced endothelial proliferation and repair in scratch-wounded HUVECs, SB203580 increased the cell proliferation and wound healing. Formononetin accelerate wound closure rate as early as day 3 after surgery and consistently observed until day 10 after in wound animal model. These data suggest that formononetin promotes endothelial repair and wound healing in a process involving the over-expression of Egr-1 transcription factor through the regulation of the ERK1/2 and p38 MAPK pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Early Growth Response Protein 1 / biosynthesis*
  • Early Growth Response Protein 1 / genetics
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology
  • Endothelial Cells / immunology
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • Isoflavones / administration & dosage
  • Isoflavones / pharmacology
  • Isoflavones / therapeutic use*
  • Mice
  • Mice, Nude
  • Molecular Structure
  • Muscle, Skeletal / blood supply
  • Muscle, Skeletal / drug effects
  • Neovascularization, Physiologic / drug effects
  • Phosphorylation
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Skin / blood supply
  • Skin / injuries
  • Skin / pathology
  • Wound Healing / drug effects*
  • Wounds, Penetrating / drug therapy*
  • Wounds, Penetrating / enzymology
  • Wounds, Penetrating / immunology
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Early Growth Response Protein 1
  • Isoflavones
  • formononetin
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases