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].