Lactate stimulation of macrophage-derived angiogenic activity is associated with inhibition of poly(ADP-ribose) synthesis

Injury and inflammation lead to hypoxia and elevated lactate in wounds. This redox environment establishes cells in a reparative phenotype and leads macrophages to release angiogenic substances by unclear mechanisms. We investigated compounds known to modulate polyadenosine diphophoribose (pADP- R) levels in their effect on macrophage-derived angiogenic activity. Macrophages cultured from rabbit bone marrow were exposed to lactate, nicotinamide, and/or β-nicotinamide adenine dinucleotide (NAD⁺). Supernatants were assayed for angiogenesis, and macrophages were analyzed for NAD⁺ content, poly(ADP-ribose) synthetase activity, and total (ADP- ribose)(n) synthesis. Lactate-, nicotinamide-, and lactate and nicotinamide- treated macrophages elicited significantly increased angiogenic activity compared with control or NAD⁺-treated cells. Lactate treatment decreased NAD⁺ content by 42 ± 4% and (ADP-ribose)(n) synthesis by 37 ± 5%. Nicotinamide reduced poly(ADP-ribose) synthetase activity and poly(ADP- ribose) synthesis. Thus, macrophage-derived angiogenic activity may be mediated by the redox environment involving NAD⁺ metabolites.