Epidermal sensing of oxygen is essential for systemic hypoxic response.
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.
Boutin
Adam T
AT
Molecular Biology Section, Division of Biological Sciences, UC San Diego, La Jolla, CA 92093, USA.
Weidemann
Alexander
A
Fu
Zhenxing
Z
Mesropian
Lernik
L
Gradin
Katarina
K
Jamora
Colin
C
Wiesener
Michael
M
Eckardt
Kai-Uwe
KU
Koch
Cameron J
CJ
Ellies
Lesley G
LG
Haddad
Gabriel
G
Haase
Volker H
VH
Simon
M Celeste
MC
Poellinger
Lorenz
L
Powell
Frank L
FL
Johnson
Randall S
RS
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
D051793:Hypoxia-Inducible Factor 1; D004921:Erythropoietin; D009569:Nitric Oxide; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D010100:Oxygen