Cyclic mechanical stretch (CMS) causes vascular smooth muscle cell proliferation, cell death and migration, resulting in vascular remodeling and subsequent vascular failure during hypertension. However, the effect of CMS on gene induction in cardiovascular disease remains to be determined. We previously demonstrated that CMS caused cell death in rat aortic smooth muscle cells (RASMCs) in a JNK- and p38-dependent manner. To explore the causal role of CMS in initiating cell death signaling and MAPK-related events, we examined the transcript profiles of CMS-induced RASMCs using cDNA microarrays and found that NR4A1 expression levels were significantly increased in response to CMS. Quantitative polymerase chain reaction (qPCR) analysis demonstrated that this increase was p38-dependent. Moreover, NR4A1 inhibition by the inhibitor CDIM8 strongly increased CMS-induced cell death in RASMCs. Considering that hypertension acts on the vascular smooth muscle cells, we also examined NR4A1 expression in arteries using an abdominal aortic constriction (AAC) mouse model. We confirmed that the NR4A1 expression was increased by hypertension in arteries subjected to AAC as compared to sham-operated arteries. From above results, we conclude that NR4A1 protects RASMCs from CMS-stimulated cell death via the p38 signal pathway.