FOXO1 regulates VEGFA expression and promotes angiogenesis in healing wounds

J Pathol. 2018 Jul;245(3):258-264. doi: 10.1002/path.5075. Epub 2018 Apr 20.


Angiogenesis is a critical aspect of wound healing. We investigated the role of keratinocytes in promoting angiogenesis in mice with lineage-specific deletion of the transcription factor FOXO1. The results indicate that keratinocyte-specific deletion of Foxo1 reduces VEGFA expression in mucosal and skin wounds and leads to reduced endothelial cell proliferation, reduced angiogenesis, and impaired re-epithelialization and granulation tissue formation. In vitro FOXO1 was needed for VEGFA transcription and expression. In a porcine dermal wound-healing model that closely resembles healing in humans, local application of a FOXO1 inhibitor reduced angiogenesis. This is the first report that FOXO1 directly regulates VEGFA expression and that FOXO1 is needed for normal angiogenesis during wound healing. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: FOXO; VEGF; angiogenesis; blood vessel; dermal; endothelial; forkhead; minipig; mucosa; skin; vascular endothelial growth factor-A; wound.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Disease Models, Animal
  • Female
  • Forkhead Box Protein O1 / deficiency
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / metabolism*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Gingiva / injuries
  • Gingiva / metabolism*
  • Gingiva / pathology
  • Humans
  • Keratinocytes / metabolism
  • Keratinocytes / pathology
  • Male
  • Mice, Knockout
  • Mouth Mucosa / injuries
  • Mouth Mucosa / metabolism*
  • Mouth Mucosa / pathology
  • Neovascularization, Physiologic*
  • Signal Transduction
  • Skin / injuries
  • Skin / metabolism*
  • Skin / pathology
  • Swine
  • Swine, Miniature
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*
  • Wound Healing*
  • Wounds and Injuries / genetics
  • Wounds and Injuries / metabolism*
  • Wounds and Injuries / pathology


  • FOXI1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse