HIF-1α coordinates lymphangiogenesis during wound healing and in response to inflammation

FASEB J. 2012 Mar;26(3):1027-39. doi: 10.1096/fj.11-195321. Epub 2011 Nov 8.


This study aimed to investigate the mechanisms that coordinate lymphangiogenesis. Using mouse models of lymphatic regeneration and inflammatory lymphangiogenesis, we explored the hypothesis that hypoxia inducible factor-α (HIF-1α) is a central regulator of lymphangiogenesis. We show that HIF-1α inhibition by small molecule inhibitors (YC-1 and 2-methyoxyestradiol) results in delayed lymphatic repair, decreased local vascular endothelial growth factor-C (VEGF-C) expression, reduced numbers of VEGF-C(+) cells, and reductions in inflammatory lymphangiogenesis. Using transgenic HIF-1α/luciferase mice to image HIF-1α expression in real time in addition to Western blot analysis and pimonidazole staining for cellular hypoxia, we demonstrate that hypoxia stabilizes HIF-1α during initial stages of wound repair (1-2 wk); whereas inflammation secondary to gradients of lymphatic fluid stasis stabilizes HIF-1α thereafter (3-6 wk). In addition, we show that CD4(+) cell-mediated inflammation is necessary for this response and regulates HIF-1α expression by macrophages, as CD4-deficient or CD4-depleted mice demonstrate 2-fold reductions in HIF-1α expression as compared to wild-types. In summary, we show that HIF-1α is a critical coordinator of lymphangiogenesis by regulating the expression of lymphangiogenic cytokines as part of an early response mechanism to hypoxia, inflammation, and lymphatic fluid stasis.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • CD4 Antigens / genetics
  • CD4 Antigens / metabolism
  • Cell Hypoxia
  • Edema / genetics
  • Edema / metabolism
  • Edema / physiopathology
  • Female
  • Gene Expression
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Immunohistochemistry
  • Indazoles / pharmacology
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / physiopathology*
  • Lymph / metabolism
  • Lymph / physiology
  • Lymphangiogenesis / drug effects
  • Lymphangiogenesis / genetics
  • Lymphangiogenesis / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor C / genetics
  • Vascular Endothelial Growth Factor C / metabolism
  • Wound Healing / drug effects
  • Wound Healing / genetics
  • Wound Healing / physiology*


  • CD4 Antigens
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indazoles
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C
  • 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole