Objective To investigate the mechanical response of Emerin, a nuclear envelope protein, and its role in apoptosis of vascular smooth muscle cells (VSMCs) during cyclic stretch, and the potential effect of transcriptional factors in this process. Methods Physiological cyclic stretch with the magnitude of 5% and frequency of 1.25 Hz was subjected to VSMCs in vitro by using FX-5000T cyclic stretch loading system. VSMCs cultured under the same conditions but without applying mechanical stretch were used as the static control. The apoptosis of VSMCs was detected by using Cleaved-caspase3 ELISA kit, and the expression of Emerin was revealed by using Western blotting. The effects of Emerin on activities of 345 kinds of transcriptional factors in VSMCs were demonstrated with Protein/DNA array after Emerin specific RNA interference (RNAi) under static condition, and the potential transcriptional factors involved in VSMC apoptosis were analyzed with Ingenurity Pathway Analysis (IPA) software. Furthermore, the binding abilities of Emerin to the motif of 2 kinds of apoptosis-related transcriptional factors were detected with chromatin immunoprecipitation (CHIP) and qPCR. ResultsCompared with the static control, the apoptosis of VSMCs was significantly decreased by 5% cyclic stretch, which suggested a protective effect of physiological cyclic stretch. The expressions of Emerin in VSMCs was remarkably increased with 5% cyclic stretch applied for 6 h, 12 h and 24 h. Specific RNAi under static condition decreased the expressions of Emerin but increased the apoptosis of VSMCs. Emerin siRNA transfection remarkably increased (more than 2 times) the activities of 10 transcriptional factors that participated in cellular apoptosis, i.e. CREB-BP1, p300, p55, MAX, NRF-1, STAT1, STAT3, TEF1, TR and BZP. CHIP-qPCR result revealed that the binding ability of Emerin to specific mofit of STAT1 or STAT3 was significantly repressed with Emerin RNAi. Conclusions Physiological cyclic stretch could increase the expression of Emerin which might modulate the binding of Emerin to motifs of apoptosis-related transcriptional factors such as STAT1 and STAT3, regulate the activities of these factors, and then subsequently repress the VSMC apoptosis. The investigation on mechanobiological mechanisms of VSMC apoptosis induced by cyclic stretch may contribute to further understanding the physiological and pathological mechanisms of vascular homeostasis and vascular remodeling.