Background and Objectives; Cell stretch and hypoxia are important stimuli for developing to hypertrophy and atherosclerotic change of heart and blood vessel. But, although, strectch-induced cardioprotection may share a common mechanism with ischemic injury, the role of MAPK was not clear and remains dispute for difference of survival- apoptosis signaling. Here, we examine whether the effect on cell signals pathways including MAPK, survival and apoptosis related to cellular response to stretch and ischemia. Method and Results; Membrane stretch model of in vitro cultured VSMC and HEK 293 cell was established for the study. The cells were processed by non-sugar hypoxic stimuli to hypoxic injuries and membrane stretch induces by hypo-osmotic injury with adding distilled H2O. The cells were then divided into normal control (N), 20%, 50% osmotic stretch (OS), ischemic and hypoxic culture (IHC), and isoproterenol (ISO) group. We evaluate on the phosphorylation of signaling molecules ERK (extracellular regulated-signaling kinase) 1/2, AKT and apoptosis signaling among groups using a Western blot, FACS. The expression phosphorylation of ERK 1/2, increased in OS group, IHC and ISO group than control group (p < 0.01). But, phosphorylation of AKT signaling was decreased in IHC groups and significant different between OS and IHC (p<0.05). The expression of apoptosis was similar result among cell injury groups and significant increased than control (p<0.05). Conclusion; Down regulation of MAPK (especially ERK) expression by stretch and hypoxia was similar but some dissociation between ERK and survival signaling AKT pathway was shown in IHC. This dissociation might be possible to relate with other signaling pathway except PIK-AKT-apoptosis signaling.