UC San Diego

This research explores a novel function of mammalian skin in sensing and responding to a hypoxic environment. Skin plays an essential role in the response and adaptation to environmental stimuli such as heat, that is mediated in part by its remarkable vascular plasticity. Some vertebrates 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-1[alpha] blocks erythropoietin (EPO) synthesis, an important aspect of the systemic hypoxic response. 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 (NO), a vasodilator and product of the inducible NO synthase gene (iNOS), a downstream target of HIF, can act on cutaneous vascular flow to increase renal erythropoietin expression through a novel physiological mechanism. The complexity of the regulation of EPO production by the skin is exemplified by data showing that an acute hypoxic response can also reduce renal EPO production by dermal vasoconstriction. These results together demonstrate that in mice, the skin is a critical mediator of systemic responses to environmental oxygen. In the third chapter, I demonstrate the critical importance of skin vasodilation state in thermoregulation and energy balance. We created a mouse model with a deletion of the tumor suppressor gene VHL in the epidermis; this deletion results in up- regulation of the HIF transcriptional pathway of hypoxic response. Because of the increase in HIF-driven gene expression, the mutation gives rise to striking increases in skin vasculature and blood flow. This altered vascular flow in the skin affects the systemic physiology to an unexpected degree; growth is stunted and lifespan severely shortened. This is the result of profound and sustained heat loss though the dilated blood vessels of the skin. Through this mutant mouse we have demonstrated the critical importance of skin blood flow in thermoregulation, and developed the first genetic animal model of hypothermia. In the fourth chapter, I connect the phenotype of NO induced skin vasodilation, described above, to a human phenomenon of clinical importance: septic shock