Abstract
The vascular endothelial growth factor (VEGF) is produced in response to hypoxia or inflammatory cytokines. In normoxia VEGF synthesis is upregulated by 15-deoxy-Δ 12,14-prostaglandin-J 2 (15d-PGJ 2) via induction of heme oxygenase-1 (HO-1). Here we compared the influence of 15d-PGJ 2 on VEGF expression in human microvascular endothelial cells in normoxia (∼20% O 2) and hypoxia (∼2% O 2). Regardless of the oxygen concentration, 15d-PGJ 2 inhibited activity of hypoxia inducible factor-1 (HIF-1), the major hypoxic regulator of VEGF. However, in normoxic conditions 15d-PGJ 2 (1–10 μM) activated the VEGF promoter and increased synthesis of the VEGF protein. Concomitantly, it strongly induced expression of HO-1. In contrast, in hypoxia, 15d-PGJ 2 decreased VEGF promoter activity and reduced VEGF release by 50%. Inhibition of HO-1 activity additionally attenuated VEGF synthesis in hypoxia. We conclude that induction of HO-1 by 15d-PGJ 2 results in augmentation of VEGF synthesis in normoxia. In hypoxia, however, the stimulatory effect of HO-1 is outweighed by 15d-PGJ 2-mediated inhibition of the HIF-1 pathway.
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