Backgrounds: Low density lipoproteins (LDL) play important roles in the pathogenesis of atherosclerosis. Diabetes is associated with accelerated atherosclerosis leading to cardiovascular disease in diabetic patients. Although LDL stimulates the proliferation and migration of vascular smooth muscle cells (SMC), the mechanisms are not fully understood. Methods and Results: We first examined the effects of native LDL and glycated LDL on the extracellular signal-regulated kinase (ERK) pathway. Addition of native and glycated LDL to rat aorta SMCs (RASMCs) stimulated ERK phosphorylation. ERK phosphorylation in response to glycated LDL was reduced by inhibition of protein kinase C (PKC) with GF109203X, inhibition of Src kinase with PP1 (5 mM) and inhibition of phospholipase C (PLC) with U73122/U73343 (5 mM), but not affected by exposure to the Ca2+ chelator, BAPTA-AM. In addition, pretreatment of the RASMCs with a cell-permeable mitogen-activated protein kinase kinase (MEK) inhibitor (PD98059, 5 mM) markedly decreased ERK phosphorylation in response to native and glycated LDL. We also investigated migration effect of glycated LDL to determine whether FAK tyrosine phosphorylation and its upstream signaling molecules were affected in SMC. Glycated LDL (50-200 mg/ml) resulted in a dose-dependent increase in RASMCs migration and glycated LDL (200 mg/ml) phosphorylated FAK at Tyr-125 at time ranging from 1 to 20 min. p125FAK phosphorylation by glycated LDL was significantly inhibited by Src kinase inhibitor, PLC inhibitor or intracellular calcium chelator but not PKC inhibitor. Based on these observations, we demonstrates that glycated LDL stimulates the proliferation and migration through Src kinase and PLC and that FAK phosphorylation could induce migration via increased intracellular Ca2+ by PLC activation but not proliferation in vitro. Inhibiting Src or PLC activity could reduce p125FAK induced SMC migration. Conclusions:We provide the first evidence that mechanisms of glycated LDL on SMC proliferation and migration may provide a new insight into the progression of atherosclerosis in diabetic patients.