| First Author | Zampell JC | Year | 2012 |
| Journal | FASEB J | Volume | 26 |
| Issue | 3 | Pages | 1027-39 |
| PubMed ID | 22067482 | Mgi Jnum | J:182809 |
| Mgi Id | MGI:5316920 | Doi | 10.1096/fj.11-195321 |
| Citation | Zampell JC, et al. (2012) HIF-1alpha coordinates lymphangiogenesis during wound healing and in response to inflammation. FASEB J 26(3):1027-39 |
| abstractText | 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-alpha (HIF-1alpha) is a central regulator of lymphangiogenesis. We show that HIF-1alpha 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-1alpha/luciferase mice to image HIF-1alpha expression in real time in addition to Western blot analysis and pimonidazole staining for cellular hypoxia, we demonstrate that hypoxia stabilizes HIF-1alpha during initial stages of wound repair (1-2 wk); whereas inflammation secondary to gradients of lymphatic fluid stasis stabilizes HIF-1alpha thereafter (3-6 wk). In addition, we show that CD4(+) cell-mediated inflammation is necessary for this response and regulates HIF-1alpha expression by macrophages, as CD4-deficient or CD4-depleted mice demonstrate 2-fold reductions in HIF-1alpha expression as compared to wild-types. In summary, we show that HIF-1alpha 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. |
