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HIF‐1α: coordinates lymphangiogenesis during wound healing and in response to inflammation
Author(s) -
Zampell Jamie C.,
Yan Alan,
Avraham Tomer,
Daluvoy Sanjay,
Weitman Evan S.,
Mehrara Babak J.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-195321
Subject(s) - lymphangiogenesis , lymphatic system , inflammation , wound healing , lymphatic endothelium , vascular endothelial growth factor c , hypoxia inducible factors , lymphatic vessel , cancer research , hypoxia (environmental) , microbiology and biotechnology , immunology , vascular endothelial growth factor , biology , pathology , vascular endothelial growth factor a , medicine , chemistry , vegf receptors , metastasis , cancer , biochemistry , organic chemistry , oxygen , gene
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.—Zampell, J. C., Yan, A., Avraham, T., Daluvoy, S., Weitman, E. S., Mehrara, B. J. HIF‐1α coordinates lymphangiogenesis during wound healing and in response to inflammation. FASEB J. 26, 1027‐1039 (2012). www.fasebj.org