Stretch-induced endothelin-1 production by astrocytes

Astrocytes proliferate during central nervous system (CNS) development and then remain quiescent. However, at a site of brain injury, astrocytes re-enter the cell cycle and undergo complex biochemical/functional changes known as reactive gliosis. Gliosis is the most important histopathologic indicator of CNS injury, regardless of etiology. Endothelins (ETs) have powerful mitogenic effects on astrocytes and have recently been implicated in the induction of gliosis. Reactive astrocytes produce, store, secrete and bind endothelin-1 (ET-1). The stimuli responsible for activating ET production in astrocytes are unresolved. Because of the relationship between stretch and ET production in other cell types, and the observation that ET-1-positive reactive astrocytes appear in mechanically deformed regions, we are examining whether mechanical deformation affects ET-1 production. We expose mature rat astrocyte cultures to mechanical stress using flexible-bottomed culture plates. Mechanical stretch of quiescent, confluent cultures causes an increase in cytoplasmic Ca²⁺ and inositol trisphosphate (IP₃), and a substantial increase in ET-1 production and secretion into the culture media.