Ethoxidine, a benzo[c]phenanthridine derivative, has been identified as a potent inhibitor\nof topoisomerase I in cancer cell lines. Our group has reported paradoxical properties of ethoxidine\nin cellular processes leading to angiogenesis on endothelial cells. Because low concentration\nethoxidine is able to favor angiogenesis, the present study aimed to investigate the ability of 10âË?â??9 M\nethoxidine to modulate neovascularization in a model of mouse hindlimb ischemia. After inducing\nunilateral hindlimb ischemia, mice were treated for 21 days with glucose 5% or with ethoxidine,\nto reach plasma concentrations equivalent to 10ââ?¬â??9 M. Laser Doppler analysis showed that recovery\nof blood flow was 1.5 fold higher in ethoxidine-treated mice in comparison with control mice.\nFurthermore, CD31 staining and angiographic studies confirmed an increase of vascular density\nin ethoxidine-treated mice. This ethoxidine-induced recovery was associated with an increase of\nNO production through an enhancement of eNOS phosphorylation on its activator site in skeletal\nmuscle from ischemic hindlimb. Moreover, real-time RT-PCR and western blots have highlighted that\nethoxidine has pro-angiogenic properties by inducing a significant enhancement in vegf transcripts\nand VEGF expression, respectively. These findings suggest that ethoxidine could contribute to favor\nneovascularization after an ischemic injury by promoting the NO pathway and VEGF expression.
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