Aim The present study aims to investigate whether BMSCs transplantation may inhibit hypertrophic hearts and its underlying mechanisms.Background There is no evidence so far that Bone marrowderived mesenchymal stem cells (BMSCs) can heal pathological myocardial hypertrophy.Methods To observe the antihypertrophic actions, BMSCs was indirectly cocultured with NRVCs in vitro, or intramyocardially transplanted into hypertrophic hearts in vivo.Results ISOinduced typical hypertrophic characteristics of cardiomyocytes were obviously prevented by BMSCs in the coculture model in vitro and after BMSCs transplantation in vivo.Furthermore, the activation 2of the Ca2+ /calcineurin/NFATc3 hypertrophic pathway was shown abrogated in the presence of BMSCs both in vitro and in vivo.Interestingly, blockage of VEGF release from BMSCs but not bFGF and IGF1 can abolish the protective effects of BMSCs on cardiomyocytes hypertrophy.Consistently, VEGF administration attenuated ISOinduced the enlargement of cellular size, the augment of ANP, BNP and βMHC expression and the activation of Ca2+/calcineurin/NFATc3 hypertrophic pathway, and these can be abrogated by blocking VEGFR1, indicating VEGFR1is involved in the antihypertrophic role of VEGF.We further find that the ample VEGF secretion contributing to the antihypertrophic effects of BMSCs originates from BMSCs interplay with cardiac cells but not BMSCs or cardiomyocytes alone.Conclusions Thus, mesenchymal stem cells are able to inhibit myocardial hypertrophy via interacting with cardiomyocytes so as to promote VEGF release which inhibits the activation of the Ca2+/calcineurin/NFATc3hypertrophic signaling pathway in cardiac cells, in addition to its wellrecognized ability to ameliorate myocardial injuries by replacing dead cells.