title: Epidermal sensing of oxygen is essential for systemic hypoxic response.
abstract: Skin plays an essential role, mediated in part by its remarkable vascular plasticity, in adaptation to environmental stimuli. Certain vertebrates, such as amphibians, respond to hypoxia in part through the skin; but it is unknown whether this tissue can influence mammalian systemic adaptation to low oxygen levels. We have found that epidermal deletion of the hypoxia-responsive transcription factor HIF-1alpha inhibits renal erythropoietin (EPO) synthesis in response to hypoxia. Conversely, mice with an epidermal deletion of the von Hippel-Lindau (VHL) factor, a negative regulator of HIF, have increased EPO synthesis and polycythemia. We show that nitric oxide release induced by the HIF pathway acts on cutaneous vascular flow to increase systemic erythropoietin expression. These results demonstrate that in mice the skin is a critical mediator of systemic responses to environmental oxygen.
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: Adam T
authors.initials: AT
authors.lastname: Boutin
authors.forename: Alexander
authors.initials: A
authors.lastname: Weidemann
authors.forename: Zhenxing
authors.initials: Z
authors.lastname: Fu
authors.forename: Lernik
authors.initials: L
authors.lastname: Mesropian
authors.forename: Katarina
authors.initials: K
authors.lastname: Gradin
authors.forename: Colin
authors.initials: C
authors.lastname: Jamora
authors.forename: Michael
authors.initials: M
authors.lastname: Wiesener
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Koch
authors.forename: Lesley G
authors.initials: LG
authors.lastname: Ellies
authors.forename: Gabriel
authors.initials: G
authors.lastname: Haddad
authors.forename: Volker H
authors.initials: VH
authors.lastname: Haase
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.forename: Lorenz
authors.initials: L
authors.lastname: Poellinger
authors.forename: Frank L
authors.initials: FL
authors.lastname: Powell
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001774:Blood Chemical Analysis; D004817:Epidermis / Q000502:physiology*; D004921:Erythropoietin / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000097:blood; D010100:Oxygen / Q000097:blood / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051793:Hypoxia-Inducible Factor 1; D004921:Erythropoietin; D009569:Nitric Oxide; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D010100:Oxygen