Sensing hypoxia

Tissue hypoxia induces a variety of physiological responses in addition to activation of the Epo-EpoR pathway (see below). Parallel responses include the stimulation of new blood vessels by vascular endothelial growth factor (VEGF) and metabolic changes (e.g. in glycolytic pathway enzymes) that enable continued energy production despite inadequate oxygen availability. In addition, expression of the transferrin receptor is upregulated. Over the past few years the mechanisms by which cells sense hypoxia and orchestrate their response have been discovered. It has been shown that the most important mediator of this cellular response is a transcription factor called HIF (hypoxia-inducible factor), which activates the genes that influence the adaptive responses to hypoxia including those encoding Epo, glycolytic pathway enzymes, transferrin receptor and VEGF (Figure 2.6).

Hypoxia

HIF1-a HIF1-P

EpoR Erythropoiesis

Supply of iron

High O2

Prolyl hydroxylase oxygen sensor

VEGF Angiogenesis

Supply of energy

Oxygenation i

Supply of energy

>

r

J

Degradation

via

proteasome

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