In chronic hypoxia, glucose availability and hypoxic severity dictate the balance between HIF-1 and HIF-2 in astrocytes.

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Astrocyte function is an important contributor to cellular viability during brain hypoxia and ischemia. Levels of the hypoxia-inducible transcription factors (HIFs) HIF-1 and HIF-2 are increased in hypoxic conditions and impact the neuroprotective properties of astrocytes. For example, HIF-2 induces levels of erythropoietin (EPO), a neuroprotectant, by astrocytes. In contrast, HIF-1 activity in astrocytes diminishes the viability of neurons in cocultures during hypoxia. Thus, HIF-1 and HIF-2 may have opposing effects on astrocytes. In this study, we explore the balance of HIF-1 and HIF-2 signaling in astrocytes during chronic (1-7 d) hypoxia while altering the degree of hypoxia and glucose availability. In addition, we investigate the effects of these conditions on neuron apoptosis. During exposure to chronic moderate hypoxia (2% O2) and plentiful glucose (10 mM), HIF-2 and EPO abundance increases from d 1 to 7. Similarly, pretreatment with moderate hypoxia markedly increases the abundance of HIF-2 and EPO when astrocytes are subsequently exposed to severe hypoxia (0.5% O2; 24 h) in 10 mM glucose, which inhibits neuron apoptosis in coculture. Although HIF-1 targets the expression increase during the 7 d in chronic moderate hypoxia (2% O2) and limited glucose (2 mM), further exposure to severe hypoxia (0.5% O2; 24 h) induces a decrease of most HIF-1 targets in astrocytes. Notably, in astrocyte exposure to 2% O2 prior to 0.5% O2, the expression of iNOS, an HIF-1-regulated protein, keeps increasing when glucose is limited, whereas EPO and VEGF abundance is suppressed, inducing increased apoptosis of neurons in coculture under limited glucose (2 mM). Thus, both hypoxic severity and glucose abundance regulate the balance of HIF-1 and HIF-2 activity in astrocytes, leading to diverse effects on neurons. These results could have important implications on the adaptive or pathologic role of astrocytes during chronic hypoxia and ischemia.-Guo, M., Ma, X., Feng, Y., Han, S., Dong, Q., Cui, M., Zhao, Y. In chronic hypoxia, glucose availability and hypoxic severity dictate the balance between HIF-1 and HIF-2 in astrocytes.