Skin plays an essential role, mediated in part by its remarkable vas
cular plasti
city, in adaptation to environmental stimuli. Certain vertebrates, su
ch as amphibians, respond to hypoxia in part through the skin; but it is unknown whether this tissue
can influen
ce mammalian systemi
c adaptation to low oxygen levels. We have found that epidermal deletion of the hypoxia-responsive trans
cription fa
ctor
HIF-1c=""http://www.sciencedirect.com/scidirimg/entities/204e.gif"" alt=""greek small letter alpha"" title=""greek small letter alpha"" border=""0""> inhibits renal erythropoietin (EPO) synthesis in response to hypoxia. Conversely, mi
ce with an epidermal deletion of the von Hippel-Lindau (VHL) fa
ctor, a negative regulator of HIF, have in
creased EPO synthesis and poly
cythemia. We show that nitri
c oxide release indu
ced by the HIF pathway a
cts on
cutaneous vas
cular flow to in
crease systemi
c erythropoietin expression. These results demonstrate that in mi
ce the skin is a
criti
cal mediator of systemi
c responses to environmental oxygen.