Hypoxia in vivo is associated with constriction of the distal vasculature in the lung. Uniquely situated at the interface between blood and the vessel wall proper, the vascular endothelium may release vasoactive mediators in the setting of hypoxia. Endothelin-1 is a potent vasoconstrictor released by endothelial cells that could function as a paracrine regulator of vascular tone. We found that physiologic low oxygen tension (PO2 = 30 Torr) increased endothelin secretion from cultured human endothelial cells four to eightfold above the secretion rate at ambient oxygen tension. This increase in secretion was accompanied by a corresponding increase in the transcriptional rate of the preproendothelin gene resulting in increased steady-state mRNA levels of preproendothelin. In contrast, the transcription of a number of other growth-factor-encoding genes, including transforming growth factor-beta, was unaffected by hypoxia. Endothelin transcript production increased within 1 h of hypoxia and persisted for at least 48 h. In addition, the stimulatory effects of low oxygen tension on endothelin mRNA levels were reversible upon reexposure to 21% oxygen environments. These findings suggest a role for endothelin in the control of regional blood flow in the vasculature in response to changes in oxygen tension.