REGULATION OF ANGIOGENIC GROWTH-FACTOR EXPRESSION BY HYPOXIA, TRANSITION-METALS, AND CHELATING-AGENTS

Recent work has indicated that oxygen-sensing mechanism(s) resembling those controlling erythropoietin production operate in many non-erythr opoietin-producing cells. To pursue the implication that such a system might control other genes, we studied oxygen-regulated expression of mRNAs for vascular endothelial growth factor, platelet-derived growth factor (PDGF) A and B chains, placental growth factor (PLGF), and tran sforming growth factor in four different cell lines and compared the c haracteristics with those of erythropoietin regulation. Oxygen-regulat ed expression was demonstrated for each gene in at least one cell type . However, the response to hypoxia (1% oxygen) varied markedly, rangin g from a 13-fold increase (PDGF-B in Hep G2 cells) to a 2-fold decreas e (PLGF in the trophoblastic line BeWo). For each gene/cell combinatio n, both the magnitude and direction of the response to hypoxia were mi micked by exposure to cobaltous ions or two different iron-chelating a gents, desferrioxamine and hydroxypyridinones. These similarities with established characteristics of erythropoietin regulation indicate tha t a similar mechanism of oxygen sensing is operating on a variety of v ascular growth factors, and they suggest that chelatable iron is close ly involved in the mechanism.