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Introduction Endothelial damage/dysfunction is a key event in cardiovascular pathological changes and development of ischaemic vascular disease, which is often followed by smooth muscle cell (SMC) proliferation and accumulation. If we could arbitrarily convert SMCs into endothelial cells (ECs), they may represent a promising new approach to achieve therapeutic angiogensis of ischaemic area. To test this hypothesis, the aim of the present study is to transdifferentiate human SMCs into functional ECs. Methods and results Human SMCs were first reprogrammed for 4 days to obtain a partially converted state, i.e. vascular progenitor, by introducing four transcription factors: Oct4, Sox2, Klf4 and c-Myc . These vascular progenitors were then subjected to defined media and culture conditions to induce endothelial lineage differentiation. The differentiated cells expressed EC markers such as CD31, CD144, and eNOS at the mRNA and protein level. Next, CD34 positive cells were selected from the heterogeneous population of vascular progenitors and further cultured in endothelial inducing conditions. The CD34+ cells were able to give rise to a more homogenous endothelial-like population in higher efficiency. The converted ECs displayed typical endothelial functional properties including acetylated-LDL uptake and tube formation in vitro and in vivo. More importantly, these ECs-derived from human SMCs exhibited therapeutic angiogenesis capacity which improved blood flow recovery when applied in the murine ischaemic hindlimb model. To explore the mechanisms involved in SMCs to ECs transdifferentiation, whole mRNAs from different reprogrammed cells were analysed by RNA-Sequencing techniques. Comprehensive analysis indicated that mesenchymal-to-epithelial transition was requisite to initiate SMCs reprogramming to vascular progenitor. Furthermore, it was demonstrated that hairy and enhancer of split 5 (HES5), a member of a family of basic helix-loop-helix transcriptional factor of the Notch signalling pathway, regulated progenitors to endothelial lineage differentiation. Conclusions In this study, we provided the first evidence of converting human SMCs towards functional EC lineage involving the mechanisms of mesenchymal-to-epithelial transition and the Notch signalling pathway. Furthermore, the converted ECs displayed a therapeutic capacity of angiogenesis in a murine ischaemic model.