Lactate elicits vascular endothelial growth factor from macrophages: a possible alternative to hypoxia

Macrophages respond to various stimuli to produce angiogenic factors but fe w mechanistic details are known. We examined the effects of hypoxia, lactat e and nicotinamide on the expression of vascular endothelial growth factor by cultured macrophages. These agents were chosen because they down-regulat e polyadenosine diphosphoribose levels. Following exposure, conditioned med ia were analyzed for vascular endothelial growth factor protein. Nicotinami de adenine dinucleotide. polyadenosine diphosphoribose, and vascular endoth elial growth factor mRNA were measured in the cellular fraction. Angiogenic capacity of the conditioned media was tested in rabbit corneas and Matrige l implants. All three agents, hypoxia, lactate and nicotinamide, elicited significantly increased levels of vascular endothelial growth factor mRNA and vascular e ndothelial growth factor in the conditioned media, and these levels were pa ralleled by their angiogenic activity. Polyadenosine diphosphoribose in the cellular traction was correspondingly depressed. Anti-vascular endothelial growth factor antibody inhibited most of the angiogenic response whereas a nti-basic fibroblast growth factor antibody had little effect. We propose t hat redox changes associated with the alteration of cellular nicotinamide a denine dinucleotide and polyadenosine diphosphoribose are involved in lacta te-mediated VEGF expression.