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.
authors: Division of Plastic and Reconstructive Surgery and Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors: Jamie C
authors: JC
authors: Zampell
authors: Alan
authors: A
authors: Yan
authors: Tomer
authors: T
authors: Avraham
authors: Sanjay
authors: S
authors: Daluvoy
authors: Evan S
authors: ES
authors: Weitman
authors: Babak J
authors: BJ
authors: Mehrara
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D004487:Edema / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D015870:Gene Expression; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008196:Lymph / Q000378:metabolism / Q000502:physiology; D042583:Lymphangiogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D015704:CD4 Antigens; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole