Cyanide is an endogenous stimulator of endothelial cell proliferation, migration and differentiation

Cyanide is generally considered a cytotoxic molecule. However, recent studies have shown that mammalian cells - including endothelial cells - can produce cyanide from glycine via a lysosomal pathway. Studies in hepatocytes indicated that cyanide, when administered at low concentrations, or when generated from endogenous sources, exerts regulatory, rather than cytotoxic effects. Here we show that human umbilical vein endothelial cells produce detectable levels of cyanide (∼0.1 nmoles/mg protein/h), and this is enhanced by administration of glycine (1 mM). Glycine stimulates endothelial cell proliferation, migration and tube formation. Low concentrations of the cyanide releasing molecules amygdalin or mandelonitrile (100 µM) exert similar effects. On one hand, cyanide induces the upregulation of VEGF protein in endothelial cells, while on the other hand, VEGF stimulates the generation of cyanide by endothelial cells, suggesting a positive feedback. VEGF-stimulated endothelial cell ATP generation, proliferation and migration is inhibited by the cyanide scavenger hydroxycobalamin (10 µM) as well as by pharmacological agents that prevent lysosomal acidification and thus inhibit cyanide formation by the endothelial cells. In conclusion, cyanide, at low concentrations, generated by endothelial cells, acts as a proangiogenic mediator, via stimulation of the VEGF pathway and the maintenance of cellular bioenergetics.