Graphical AbstractEPC-EXs: The hallmarks and pleiotropic functions. EPC-EXs are extracellular vesicles generated by EPCs and they carry lipids, proteins, nucleic acids, metabolites, and some EPC markers. They mediate intercellular communication and affect various aspects of cell biology.

Endothelial progenitor cells (EPCs) are associated with vascular repairing and progression of atherosclerotic lesion. It may lead to coronary artery disease (CAD) if circulating EPCs lose their function. Continuous nitroglycerin (NTG) therapy causes increased vascular oxidative stress and endothelial dysfunction. The aim of this study was to investigate the effects of NTG on the proliferation of human peripheral blood-derived EPCs. EPC cultures, collected from 60 CAD patients and cultured for 7-12 days, were treated with different concentrations of NTG (0.0, 0.3, 1.0, 2.0, 7.5, 15.0, and 20.0 mg/l) for 72 h, respectively. The cell counts and proliferative activities of EPC; the levels of vascular endothelial growth factor-A (VEGF-A), nitric oxide (NO) and peroxynitrite (ONOO(-)) in culture medium; and the level of reactive oxygen species (ROS) in adherent cells were measured. Compared with control (0.0 mg/l NTG), the cell number and proliferative activities of EPCs were increased when treated with 1.0 mg/l NTG and reached maximum level when NTG concentration was 7.5 mg/l. However, there was a significant reduction when treated with higher doses of NTG (≥15.0 mg/l). Meanwhile, VEGF-A expression reached its maximal expression with 7.5 mg/l NTG, but gradually declined by incubation with higher doses of NTG. There was a linear relationship between NO level and NTG concentration, but no changes of ONOO(-) and ROS levels were found when EPCs were incubated with 0.3-7.5 mg/l NTG. However, ONOO(-) and ROS levels were significantly increased when incubated with 15 and 20 mg/l NTG. Our data demonstrated that moderate dose of NTG may stimulate the proliferative activities of EPCs isolated from CAD patients.

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