AIM We investigated the pro-angiogenic effect of S-propargyl-cysteine (SPRC), a novel water-soluble modulator of endogenous hydrogen sulfide, to provide experimental basis for angiogenesis-mediated dmg therapy of ischemic heart disease.METHODS Some models such as Transwell and Matrigel plug were carried out to determine the pro-angiogenic effect of SPRC under normal condition.Hind-limb ischemia model was induced to explore the angiogenesis in ischemic condition by laser doppler imaging and angiography.Western blot and immunofluorescence were used to detect the level and location of proteins.EMSA and CHIP were performed to determine the activation of STAT3 and its downstream promoters.RESULTS SPRC promoted cell proliferation, adhesion, migration and tube formation of primary HUVEC and increased angiogenesis ex vivo and in vivo under both normal and ischemic conditions.The former research reported H2S could directly active VEGFR2 by disrupting the disulfide bonds within it.Here, we found the interaction between VEGFR2 and STAT3 was also enhanced after SPRC-treatment.Besides, the elevated phosphorylation of STAT3 induced by SPRC could be abolished by addition of SU5416, an inhibitor of VEGFR2.In addition, SPRC induced translocation of STAT3 to nucleus, followed by transcriptional activation of downstream promoters.The critical roles of STAT3 in SPRC-induced angiogenesis were confirmed by RNA interference.CONCLUSION SPRC promoted angiogenesis under both normal and ischemic conditions, and effected through a H2S/VEGFR2/STAT3 axis.