Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema.

High-altitude cerebral edema, a serious and often fatal condition, results from lowered oxygen supply. This study explores the mechanisms by which hypoxia induces cerebral edema. We show that hypoxia induced cerebral edema and neuronal apoptosis associated with increased expression of the neuropeptide corticotrophin releasing factor (CRF) and its type 1 receptor (CRFR1), the water channel aquaporin-4 (AQP4), and endothelin-1; these effects could be blocked by the CRFR1 antagonist. In cultured astrocytes, CRF, acting through CRFR1, triggers intracellular signaling and contributes to phosphorylation and expression of AQP4 to enhance water influx into cells. These data provide an understanding of the development of cerebral edema by high-altitude hypoxia and suggest that CRFR1 might be a target molecule for prevention of this disorder.