The good, the bad, and the cell type-specific roles of hypoxia inducible factor-1α in neurons and astrocytes

Hypoxia inducible factor-1 alpha (HIF-1 alpha) is a key regulator of oxygen homeostasis, because it is responsible for the regulation of genes involved in glycolysis, erythropoiesis, angiogenesis, and apoptosis. In the CNS, HIF-1 alpha is stabilized by insults associated with hypoxia and ischemia. Because its many target genes mediate both adaptive and pathological processes, the role of HIF-1 alpha in neuronal survival is debated. Although neuronal HIF-1 alpha function has been the topic of several studies, the role of HIF-1 alpha function in astrocytes has received much less attention. To characterize the role of HIF-1 alpha in neurons and astrocytes, we induced loss of HIF-1 alpha function specifically in neurons, astrocytes, or both cell types in neuron/astrocyte cocultures exposed to hypoxia. Although loss of HIF-1 alpha function in neurons reduced neuronal viability during hypoxia, selective loss of HIF-1 function in astrocytes markedly protected neurons from hypoxic-induced neuronal death. Although the pathological processes induced by HIF-1 alpha in astrocytes remain to be defined, induction of inducible nitric oxide synthase likely contributes to the pathological process. This study delineates, for the first time, a cell type-specific action for HIF-1 alpha within astrocytes and neurons.