title: Loss of Arnt (Hif1β) in mouse epidermis triggers dermal angiogenesis, blood vessel dilation and clotting defects.
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 1α (Hif1α) along with compensatory induction of Arnt2. Ectopic induction of Arnt2 results in its heterodimerization with stabilized Hif1α 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 HIF1α 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.
authors.affiliation: Department of Dermatology, Columbia University, New York, NY, USA.
authors.forename: Assefa
authors.initials: A
authors.lastname: Wondimu
authors.forename: Lynda
authors.initials: L
authors.lastname: Weir
authors.forename: Douglas
authors.initials: D
authors.lastname: Robertson
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mezentsev
authors.forename: Sergey
authors.initials: S
authors.lastname: Kalachikov
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Panteleyev
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis / Q000737:chemistry; D001778:Blood Coagulation Disorders / Q000209:etiology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004817:Epidermis / Q000502:physiology*; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics; D055503:Protein Multimerization; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply*; D014664:Vasodilation; D014841:von Willebrand Factor / Q000502:physiology
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D011393:Procollagen-Proline Dioxygenase; D014841:von Willebrand Factor; C497397:Arnt protein, mouse; C099817:Arnt2 protein, mouse; C522722:PHD3 protein, mouse