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


Authors: Zampell, J. C.; Yan, A.; Avraham, T.; Daluvoy, S.; Weitman, E. S.; Mehrara, B. J.
Article Title: HIF-1α coordinates lymphangiogenesis during wound healing and in response to inflammation
Abstract: 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. © FASEB.
Keywords: controlled study; protein expression; unclassified drug; nonhuman; comparative study; animal cell; mouse; luciferase; inflammation; wild type; immunoregulation; hypoxia; vasculotropin c; lymphangiogenesis; wound healing; cytokine; immune response; cd4+ t lymphocyte; western blotting; staining; pimonidazole; cell hypoxia; t cell depletion; macrophage; hypoxia inducible factor 1alpha; cd4 cells; hypoxia inducible factor-1α; 2 methyoxyestradiol; blocking agent; lificiguat
Journal Title: FASEB Journal
Volume: 26
Issue: 3
ISSN: 0892-6638
Publisher: Federation of American Societies for Experimental Biology  
Date Published: 2012-03-01
Start Page: 1027
End Page: 1039
Language: English
DOI: 10.1096/fj.11-195321
PROVIDER: scopus
PUBMED: 22067482
PMCID: PMC3470728
DOI/URL:
Notes: --- - "Export Date: 2 April 2012" - "CODEN: FAJOE" - "Source: Scopus"
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MSK Authors
  1. Sanjay Daluvoy
    17 Daluvoy
  2. Babak Mehrara
    451 Mehrara
  3. Tomer Avraham
    33 Avraham
  4. Jamie Christine Zampell
    29 Zampell
  5. Alan Yan
    20 Yan
  6. Evan Scott Weitman
    18 Weitman