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 a nd leads macrophages to release angiogenic substances by unclear mecha nisms. We investigated compounds known to modulate polyadenosine dipho phoribose (pADP-R) levels in their effect on macrophage-derived angiog enic activity. Macrophages cultured from rabbit bone marrow were expos ed to lactate, nicotinamide, and/or beta-nicotinamide adenine dinucleo tide (NAD(+)). Supematants were assayed for angiogenesis, and macropha ges were analyzed for NAD(+) content, poly(ADP-ribose) synthetase acti vity, and total (ADP-ribose)(n) synthesis. Lactate-, nicotinamide-, an d 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 (AD P-ribose)(n) synthesis by 37 +/- 5%, Nicotinamide reduced poly(ADP-rib ose) synthetase activity and poly(ADP-ribose) synthesis. Thus. macroph age-derived angiogenic activity may be mediated by the redox environme nt involving NAD(+) metabolites.