OBJECTIVE Communication between endothelial and smooth muscle cells (SMCs) contributes to atherosclerosis induced by atherogenic factors, such as oxide LDL.Asymmetric dimethylarginine (ADMA), a newly found cardiovascular risk factor, accumulates in the culture medium of oxide LDL (oxLDL)-treated endothelial cells and positively correlates with atherosclerosis.We hypothesized that ADMA mediates the communication between endothelial and smooth muscle cells that is triggered by oxLDL and leads to VSMC migration (a critical role in the initiation atherosclerosis) through the activation of MAPK signal transduction.METHODS AND RESULTS Human umbilical vein endothelial cells (HUVECs) were incubated with different concentrations of oxLDL (0, 20, 40, 60, and 80 μg·ml-1) for 12 h.The conditioned mediums were collected for ADMA concentration detection.VSMC were pretreated with these conditioned medium and the migrating ability of VSMC was evaluated in the Transwell migrating assay.DDAH2, the main subtype of dimethylarginine dimethylaminohydrolase in the cardiovascular system, is the specific hydrolase of ADMA and modulates ADMA levels.To further confirm the role of the DDAH2/ADMA pathway, the strategies of DDAH2 knock-down and overexpression were applied.Results showed that ADMA were markedly accumulated in the conditioned medium (r =0.872, P < 0.01).When these conditioned medium of oxLDL-treated HUVECs were incubated with VSMC, cell migration were obviously induced.The effect of oxLDL on the accumulation of ADMA in HUVEC medium was amplified by DDAH2 knock-down and the inducing effects of HUVECconditioned medium on VSMC migration was significantly enhanced by DDAH2 knock-down as shown by the increase in the number of migrated cells.To further define the direct role of ADMA on the migration of VSMCs, exogenous ADMA was used.ADMA induced VSMC migration in a concentration-dependent manner in the concentration range of 3-30 μmol·L-1 as assessed by the confluent area of VSMCs in a wound-healing assay.Treatment of VSMCs with 10 μmol·L-1 ADMA increased VSMC migration 2.9-fold (P < 0.01).MAPK cell signaling transduction way has been found to be involved in cell migration.Our results showed that ADMA significantly activated the ERK1/2 and p38MAPK signaling transduction pathways, but not the JNK signal transduction pathway in VSMCs.CONCLUSION This study demonstrates that ADMA mediates the communication between endothelial cells and SMCs induced by oxLDL leading to SMC migration.In addition, the present study suggests exogenous ADMA directly induces SMC migration via p38 and ERK1/2 MAPK signaling transduction way.Investigations to identify the factors regulating VSMC migration may provide novel insights into atherosclerosis and its complications.