Angiogenic potency of nucleotide metabolites: potential role in ischemia-induced vascular growth

Hypoxia and ischemia are potent stimuli to vascular growth. The mechanisms by which vascular growth is induced are unknown. During ischemia, such as that which occurs in the heart, purine and pyridine nucleotides are degraded and their metabolites accumulate. At least two of these metabolites, adenosine and nicotinamide, have previously been demonstrated to induce vascular growth. The goal of this study was to determine whether other purine and pyridine metabolites have the potential to stimulate angiogenesis in vivo, to determine the relative angiogenic potency of these metabolites, and to determine if their angiogenic effects is mediated through a direct effect on endothelial cell proliferation. Purine metabolites (adenosine, inosine, hypoxanthine, xanthine, guanosine, uric acid), the pyridine metabolite nicotinamide, and chemical derivatives of nicotinamide, were tested at various concentrations for their ability to stimulate angiogenesis in the chick choriollantoic membrane assay. Although none of the purine metabolites were effective in promoting the angiogenic response, nicotinamide as well as several derivatives of nicotinamide induced an angiogenic response in a dose-dependent manner. Nicotinamide was then evaluated to determine if its angiogenic effect is a result of a direct effect on capillary endothelial cell proliferation. In concentrations of 100 microM to 1 mM nicotinamide was not demonstrated to be mitogenic for bovine capillary endothelial cells. These results demonstrate that pyridine nucleotides are indirect angiogenic agents that do not exert a primary effect on endothelial cell proliferation. The results of this study suggest that increases in vascular growth induced by ischemia and hypoxia might be mediated, at least in part, by pyridine metabolites released from ischemic tissues.