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Endothelial progenitor cells (EPCs) participate in angiogenesis and the response to chronic ischemia. Risk factors and cardiovascular disease attenuate EPC number, function, and survival. Continuous therapy with nitroglycerin (glyceryl trinitrate; GTN) is associated with increased vascular oxidative stress, leading to nitrate tolerance and endothelial dysfunction. Thus, GTN therapy may also affect EPCs. The purpose of this study was to determine whether continuous exposure to GTN in vivo or during ex vivo expansion affects the circulating number and functional characteristics of human EPCs. To determine the effects of continuous in vivo GTN exposure, EPCs isolated from 28 healthy males before and after receiving 0.6 mg/h GTN (n=17) or no treatment (n=11) for 1 week were expanded for 6 days and compared. To determine the effects of continuous ex vivo GTN exposure, EPCs isolated before randomization were expanded for 6 days in medium supplemented with 100 nM, 300 nM, or 1 microM GTN. EPCs expanded without GTN served as controls (n=10). In vivo, GTN exposure significantly increased the percentage of circulating cells expressing the EPC marker CD34 and increased the susceptibility of expanded EPCs to apoptosis but had no impact on the phenotypic differentiation or migration of EPCs. Ex vivo, GTN exposure increased apoptosis while decreasing phenotypic differentiation, migration, and mitochondrial dehydrogenase activity of EPCs, compared with EPCs expanded in the absence of GTN. Taken together, these results suggest that continuous GTN therapy might impair EPC-mediated processes, an effect that could be detrimental in the setting of ischemic cardiovascular disease.