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INTRODUCTION The present study aimed to realize human recombinant leptin 's ability to synthesize VEGF A while inducing neovascularization through PI3K/Akt/mTOR/S6 kinase involved signaling pathway. METHODS To examine the PI3K/Akt/mTOR/S6 kinase pathway involvement in leptin-induced VEGF A synthesis, the chick chorioallantoic membrane (CAM) was incubated with human recombinant leptin and specific inhibitors of the proposed signaling molecules (rapamycin and wortmannin). We analyzed the role of specified signaling molecules in human recombinant leptin-induced physiological angiogenesis via VEGF A synthesis in detail with the support of various methodologies. RESULTS Human recombinant leptin's ability to synthesize VEGF A is diminished significantly in the presence of inhibitors. This observation supported the role of PI3K/Akt/mTOR/S6 kinase signaling molecules in human recombinant leptin-mediated VEGF A synthesis while inducing angiogenesis in CAM. CONCLUSION Synthesis of VEGF A, followed by the growth of new blood vessels, by human recombinant leptin via the activation of the PI3K/Akt/mTOR/S6 kinase signaling pathway reflects mechanistic therapeutic application of human recombinant leptin. The data also signify the role of mTOR and S6 kinase molecules in angiogenesis under a physiological environment.