Loss of Arnt (Hif1 beta) in mouse epidermis triggers dermal angiogenesis, blood vessel dilation and clotting defects

Assefa Wondimu, Lynda Weir, Douglas Robertson, Alexandre Mezentsev, Sergey Kalachikov, Andrey A. Panteleyev

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    Abstract

    Targeted ablation of Aryl hydrocarbon receptor nuclear translocator (Arnt) in the mouse epidermis results in severe abnormalities in dermal vasculature reminiscent of petechia induced in human skin by anticoagulants or certain genetic disorders. Lack of Arnt leads to downregulation of Egln3/Phd3 hydroxylase and concomitant hypoxia-independent stabilization of hypoxia-induced factor 1 alpha (Hif1 alpha) along with compensatory induction of Arnt2. Ectopic induction of Arnt2 results in its heterodimerization with stabilized Hif1 alpha and is associated with activation of genes coding for secreted proteins implicated in control of angiogenesis, coagulation, vasodilation and blood vessel permeability such as S100a8/S100a9, S100a10, Serpine1, Defb3, Socs3, Cxcl1 and Thbd. Since ARNT and ARNT2 heterodimers with HIF1 alpha are known to have different (yet overlapping) downstream targets our findings suggest that loss of Arnt in the epidermis activates an aberrant paracrine regulatory pathway responsible for dermal vascular phenotype in K14-Arnt KO mice. This assumption is supported by a significant decline of von Willebrand factor in dermal vasculature of these mice where Arnt level remains normal. Given the essential role of ARNT in the adaptive response to environmental stress and striking similarity between skin vascular phenotype in K14-Arnt KO mice and specific vascular features of tumour stroma and psoriatic skin, we believe that further characterization of Arnt-dependent epidermal-dermal signalling may provide insight into the role of macro-and micro-environmental factors in control of skin vasculature and in pathogenesis of environmentally modulated skin disorders. Laboratory Investigation (2012) 92, 110-124; doi:10.1038/labinvest.2011.134; published online 26 September 2011

    Original languageEnglish
    Pages (from-to)110-124
    Number of pages15
    JournalLaboratory Investigation
    Volume92
    Issue number1
    DOIs
    Publication statusPublished - Jan 2012

    Keywords

    • Arnt2
    • Egln3/Phd3
    • Hif1 alpha
    • keratinocytes
    • S100a genes
    • vasculature
    • von Willebrand factor
    • HYPOXIA-INDUCIBLE FACTOR-1
    • ENDOTHELIAL GROWTH-FACTOR
    • NUCLEAR TRANSLOCATOR ARNT
    • ARYL-HYDROCARBON RECEPTOR
    • TUMOR-SUPPRESSOR PROTEIN
    • B-CELL DEVELOPMENT
    • VASCULAR-PERMEABILITY
    • UP-REGULATION
    • LYMPHATIC VASCULATURE
    • OXYGEN HOMEOSTASIS

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