Optical Analysis of the Oxygen-Sensing Signal Pathway

The heterogeneous oxygen partial pressure (PO2) distribution in mammalian organs ranging from about 0 to 90 torr, under normoxic conditions with an arterial PO2 of about 100 torr as shown in Figure 1, requires an O2-sensing signal cascade to adapt cellular functions to PO2 heterogeneity. Under normoxic conditions O2 sensing leads to optimization of cell function (normoxic response) as exemplified by enhanced phosphoenol pyruvate carboxykinase (PCK) expression in the periportal liver zone with high PO2 levels and of enhanced glukokinase (GK) expression in the perivenous liver zone with low PO2 levels (1). Under arterial hypoxia tissue PO2 frequency distribution is left-shifted leading to a hypoxic response of O2 sensing for adaptation of cell function. The response includes enhanced expression of an array of proteins involved in regulation of different functions such as erythropoietin (EPO) in red cell formation, vascular endothelial growth factor (VEGF) in blood vessel formation (2), or lactate dehydrogenase (LDH) in energy metabolism (3). Furthermore, potassium channel gating is altered in carotid body type I cells to release various transmitter-exciting, synaptically connected nerve fibers for nervous regulation of ventilation and blood circulation (4,5), in neuroepithelial bodies (NEB) to release serotonin controlling the bronchial muscular tone during hypoxia (6-8) as well as in vascular smooth muscle cells leading to peripheral blood vessel dilatation (9) or to lung vessel vasoconstriction (10). The anoxic response supports survival of cell function as it occurs in lower vertebrates by drastically reducing protein synthesis and thereby reducing O2 consumption enabling life for months under water without ventilation (11). Reduction of protein synthesis was also observed in the peri-infarct area (penumbra) after stroke induced by middle cerebral artery occlusion probably facilitating survival of cell function by means of oxygen sensing (12).