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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