Introduction: Restenosis represents the main drawback in the long term success of stenting procedures. Changes in vascular smooth muscle cell (SMC) proliferation and apoptosis are critical in the development of in-stent restenosis [1]. Cyclic strain is a key stimulus in the proliferative and apoptotic capacity of SMC [2]. The expansion of a comparatively stiff stent within a vessel alters the mechanical environment from low mean, high amplitude to a high mean, low amplitude cyclic strain. The aim of this work was to investigate the effect of mean strain and amplitude on the proliferation and apoptotic capacity of vascular SMC. Methods: Bovine aortic SMC were subjected to cyclic strain at different mean strains and amplitudes using a Flexercell FX-4000T™ system with an applied sinusoidal waveform before cell proliferation and apoptosis were evaluated. Vybrant™ CFDA-SE dye and Alexa Fluor 488™ Annexin V and propidium iodide were used to determine cell proliferation and apoptosis, respectively, using FACS analysis. Cell counts were also performed using a hemocytometer. Results: Bovine aortic SMC were strained at the same amplitude (2%) but at different mean strains (5% and 10%) for 48 h before levels of proliferation and apoptosis were measured. In parallel studies, cells were exposed to low mean strain (5%) and high amplitude (6%) versus high mean strain (11%) and low amplitude (2%). Changes in mean strain had no significant proliferative or apoptotic effect on SMC. In contrast, the proliferative and apoptotic capacity of SMC was highly dependent on the amplitude of the cyclic strain. A low strain amplitude (2% vs 6%) promoted cell proliferation (ANOVA, p<0.05) and inhibited apoptosis (ANOVA, p<0.05). We further validated the role of mean strain vs. amplitude using a novel bioreactor where SMCs were cultured inside a perfused stented Sylgard™ mock coronary artery in which physiological and pathological levels of strain were mimicked, see figure 1. Strains were set to be between 2% and 8% in the non-stented region. In the stented area strain was set to have amplitude between 1 and 1.5% and a mean strain increase of 25%. The level of proliferation was significantly increased in the stented region when compered to non-stented, see figure 2. Conclusions: It is the amplitude of the strain that dictates SMC behaviour rather than the mean strain in vitro. These data provide evidence for the use of more compliant stent designs in order to reduce in-stent restenosis.