PHYSIOLOGICAL RESPONSE TO HYPOXIA
The response to both acute, intermittent (repeat cycling in and out of hypoxia), and chronic hypoxia, is sensed by chemoreceptors. Peripheral chemoreceptors are chemical sensory cells in the aortic and carotid bodies that are activated by changes in oxygen, carbon dioxide, and pH levels in the blood which they communicate to the central nervous system. The response restores homeostasis by increasing ventilation, optimizing pulmonary ventilation-perfusion ratio, increasing cardiac function, and raising the oxygen carrying capacity of the blood [20, 21]. In addition to optimizing gas exchange, inadequate supply triggers hyperacute responses (seconds to minutes) of vascular beds which are initiated by mitochondria, acting as oxygen sensor [22]. A hypoxic vasomotor response leads to vasodilation and increased tissue blood flow in most organs, with the exception of the lungs, where hypoxia induces vasoconstriction. This hyperacute response is followed by a subacute response (minutes to hours), during which the master switch of cellular hypoxia defense, known as hypoxia-inducible factor (HIFs), is activated. These are proteins which mediate alterations in the expression of various hypoxia-sensitive genes such as erythropoietin (EPO), endothelin-1 and vascular endothelial growth factor (VEGF) [5, 20, 23]. HIF’s are rapidly broken down by pyrolyl-hydroxylase enzymes under normoxic conditions, but are allowed to accumulate and alter gene transcription under hypoxia due to the oxygen dependent activity of their degrading enzymes. Increased EPO and VEGF expression promote erythropoiesis and angiogenesis respectively, which augments the oxygen delivery to cells and tissues [24]. HIF-1α can also induce glucose transporter genes to improve glucose transport and metabolism [25]. Furthermore, inflammatory stimuli trigger a metabolic shift in immune cells from oxidative phosphorylation towards glycolysis [26]. Interestingly, HIF may also be activated under normoxic conditions, thus hypoxia-independent, for instance in the situation of severe systemic bacterial infection [27, 28]. Similarly, HIF activation can occur in situations mimicking hypoxia, such as severe iron deficiency [29]. Whereas HIF-1α is the dominating HIF molecule during the first 24 hours of hypoxia exposure, HIF-2α gains dominance thereafter [30]. HIF-2α upregulation contributes to serious systemic diseases like pulmonary hypertension, pulmonary and cardiac fibrosis and polycythemia [31]. Furthermore, HIF activates the transcription of genes which are pivotal for cancer genesis, progression and metastasis [32].