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Aims We tested the hypothesis that endothelial progenitor cell ( EPC)-mediated functional recovery after stroke may be associated with the endothelial nitric oxide synthase (eNOS)/brain-derived neurotrophic factor ( BDNF) signaling pathway. Methods Mice were infused with either EPCs or saline after being subjected to middle cerebral artery occlusion. The EPC-treated mice also received intravenous injections of either Nω-nitro- l-arginine methyl ester (L- NAME, the NOS inhibitor) or saline. Results The activation of eNOS and the expression of BDNF were significantly increased in ischemic brain of the EPC-treated mice, along with increased angiogenesis and neurogenesis. On diffusion tensor imaging ( DTI), significant increases in fractional anisotropy and fiber count were observed in white matter, indicating axonal growth stimulated by EPCs. However, the EPC-treated mice that were received an L- NAME injection failed to exhibit the observed increases in angiogenesis, neurogenesis, and axonal growth. In addition, the neurons cocultured with EPCs in vitro exhibited the increased expression of BDNF and decreased apoptosis after oxygen-glucose deprivation compared with the control group. This EPC-induced protective effect was virtually absent in the L- NAME treatment group. Conclusion The eNOS/ BDNF pathway may be involved in the EPC-mediated functional recovery of stroke mice. DTI is feasible for dynamically tracking the orientation of axonal projections after EPC treatment. [ABSTRACT FROM AUTHOR]