Hypoxia and hypoxia-inducible factor modulated gene expression in brain: involvement in neuroprotection and cell death.

Hypoxia, due to impaired cerebral blood flow, has hazardous effects on brain structure and function. Therefore, mechanisms should exist to meet the needs for hypoxic adaptation via regulation of gene expression. Signaling between the O2 sensor and the regulator(s) of transcription is only partially characterized and requires regulatory transcription factors. Among these regulatory proteins, hypoxia-inducible factor-1 (HIF-1) appears to have a key role. HIF-1 modulates gene activity in response to low O2 tensions in the developing and in the adult brain. Moderate hypoxia may elicit autoprotective mechanisms or hypoxia-induced regulators can contribute to mechanisms leading to cell death. Moreover, reactivation of embryonic gene expression may occur after injury-induced hypoxia. Thus, analyses of embryonic and pathogenic models should help to understand how hypoxia-mediated proliferative/cell death processes are involved in brain development and in the pathogenesis of acute or chronic neurodegenerative brain diseases.