HOXA9 regulates angiogenesis in human hypertrophic scars: induction of VEGF secretion by epidermal stem cells

Int J Clin Exp Pathol. 2014 May 15;7(6):2998-3007. eCollection 2014.


Hypertrophic scars are fibroproliferative disorders of excessive wound healing after skin injury. Vascular endothelial growth factor (VEGF)-induced angiogenesis plays a major role in fibrogenesis and hypertrophic scar formation. Over recent years, there has been a major interest in homeobox gene regulation of VEGF-VEGFR mediated angiogenesis in dermal tissue. In the current study, we investigated the role of homeobox genes in the epidermis, for their role in angiogenesis, with a focus on epidermal-mesenchymal interactions. As epidermal stem cells (ESCs) have a central role in epidermal homeostasis, we tested the hypothesis that these cells play a key role in the pathogenesis of hypertrophic scars through the HOXA9-VEGF/VEGFR signaling pathways. We found significant differences in the expression of homeobox A9 in hyperplastic scar tissue during different phases of development. These differences coincided with similar regulations in VEGF expression and with the distribution of ESCs. HOXA9 is expressed in cultured human ESCs in vitro. Antisense suppression of HOXA9 expression was found to suppress VEGF levels in ESCs. Together these findings indicate that homeobox A9 regulates the expression of VEGF in ESCs.

Keywords: Epidermal stem cells (ESCs); angiogenesis; homeobox genes; vascular endothelial growth factor (VEGF).

MeSH terms

  • Adolescent
  • Blotting, Western
  • Child
  • Child, Preschool
  • Cicatrix, Hypertrophic / metabolism*
  • Cicatrix, Hypertrophic / pathology
  • Enzyme-Linked Immunosorbent Assay
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Female
  • Fluorescent Antibody Technique
  • Homeodomain Proteins / metabolism*
  • Humans
  • Infant
  • Male
  • Neovascularization, Pathologic / metabolism*
  • RNA, Small Interfering
  • Real-Time Polymerase Chain Reaction
  • Stem Cells / metabolism*
  • Transfection
  • Vascular Endothelial Growth Factor A / metabolism*
  • Young Adult


  • Homeodomain Proteins
  • RNA, Small Interfering
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • homeobox protein HOXA9