The molecular reprogramming of astrocyte gene expression induced by oxygen deprivation is one of the astrocyte-mediated neuroprotective processes relevant to neurodegenerative diseases and various brain injury conditions. The primary oxygen sensor that mediates eukaryotic cells’ adaptive response to changes in oxygen concentration is hypoxia-inducible transcription factor 1 alpha (HIF-1α). Therefore, the astrocyte neuroprotective ability triggered by the activation of HIF-1α downstream effectors has sparked interest in hypoxia mimetics-based treatment approaches as a means to induce adaptive responses without direct hypoxia exposure. Compared to similar studies that evaluated the effect of both oxygen and glucose deprivation for several hours, this study uncovers the reprogramming of astrocyte gene expression patterns after exposure to hypoxia alone for short and relatively long periods of time − 30 min for short-term (ST) and three hours for long-term (LT) hypoxia − as well as following 24 h of reoxygenation induced recovery (RIR). The transcriptional activation of a number of genes, including Pdk1, Mct4, Sirt1, Bcl2, Hsp70, and Sod2, ends rather rapidly, only lasting over the ST-hypoxia. Conversely, during LT-hypoxia, Glut1 and Vegf1 show elevated expression, which is likely due to a positive feedback loop in which secreted Vegf increases both its own and Glut1’s expression. Interestingly, the ST-hypoxia establishes long-lasting variations of gene expression that may be essential for generating an effective neuroprotective response. This is demonstrated by the fact that Mct4 expression continues to be raised during the 24-hour normoxia period that follows the ST-hypoxia, thereby aiding in metabolic adaptation. Therefore, it is reasonable to draw the conclusion that the length of transcriptional activation varies depending on the gene and is associated with the function of the encoded protein.
The Molecular Signature of Astrocyte Response to Hypoxia Outlines the Metabolic and Cell Survival Mechanisms for Neuroprotection / Stefanelli, Roberta; Spada, Caterina; Palma, Alessandro; Canterini, Sonia; Fiorenza, Maria Teresa. - In: NEUROCHEMICAL RESEARCH. - ISSN 1573-6903. - 51:44(2026). [10.1007/s11064-025-04643-0]
The Molecular Signature of Astrocyte Response to Hypoxia Outlines the Metabolic and Cell Survival Mechanisms for Neuroprotection
Stefanelli, Roberta;Palma, Alessandro;Canterini, Sonia;Fiorenza, Maria Teresa
2026
Abstract
The molecular reprogramming of astrocyte gene expression induced by oxygen deprivation is one of the astrocyte-mediated neuroprotective processes relevant to neurodegenerative diseases and various brain injury conditions. The primary oxygen sensor that mediates eukaryotic cells’ adaptive response to changes in oxygen concentration is hypoxia-inducible transcription factor 1 alpha (HIF-1α). Therefore, the astrocyte neuroprotective ability triggered by the activation of HIF-1α downstream effectors has sparked interest in hypoxia mimetics-based treatment approaches as a means to induce adaptive responses without direct hypoxia exposure. Compared to similar studies that evaluated the effect of both oxygen and glucose deprivation for several hours, this study uncovers the reprogramming of astrocyte gene expression patterns after exposure to hypoxia alone for short and relatively long periods of time − 30 min for short-term (ST) and three hours for long-term (LT) hypoxia − as well as following 24 h of reoxygenation induced recovery (RIR). The transcriptional activation of a number of genes, including Pdk1, Mct4, Sirt1, Bcl2, Hsp70, and Sod2, ends rather rapidly, only lasting over the ST-hypoxia. Conversely, during LT-hypoxia, Glut1 and Vegf1 show elevated expression, which is likely due to a positive feedback loop in which secreted Vegf increases both its own and Glut1’s expression. Interestingly, the ST-hypoxia establishes long-lasting variations of gene expression that may be essential for generating an effective neuroprotective response. This is demonstrated by the fact that Mct4 expression continues to be raised during the 24-hour normoxia period that follows the ST-hypoxia, thereby aiding in metabolic adaptation. Therefore, it is reasonable to draw the conclusion that the length of transcriptional activation varies depending on the gene and is associated with the function of the encoded protein.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
