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Dysregulation of autophagy in endothelial cells plays a vital role in cardiovascular dysfunction and atherosclerosis. Accumulating evidence shows that miRNAs regulate autophagy in various cell types by targeting autophagy-related genes. In the present study, we found that a co-culture of human umbilical vein endothelial cells (HUVECs) with human aortic smooth muscle cells (HAoSMCs) inhibited autophagy activity in HUVECs. Furthermore, we isolated exosomes secreted by HAoSMCs, and confirmed that the exosomes contain miR-221/222. We investigated the role of miR-221/222 transferred by HAoSMC-derived exosomes in HUVECs. These exosomes induced an increase of miR-221/222 expression and a down-regulation of phosphatase and tensin homolog deleted on chromosome ten (PTEN) in HUVECs. Dual luciferase reporter assays revealed that miR-221/222 could bind to the 3′UTR of PTEN, which implied that PTEN was a direct target of miR-221/222. The expression of PTEN could be down-regulated by miR-221/222 over-expression. Then, we detected the expression of PTEN, LC3, ATG5, SQSTM1/p62, Beclin-1, Akt, and phospho-Akt in HUVECs transfected with miR-221/222 mimics and inhibitors. Our results demonstrated that miR-221/222 overexpression inhibited the expression of PTEN and subsequently activated Akt signaling, and eventually down-regulated the expression of LC3II, ATG5 and Beclin-1, and elevated the expression of SQSTM1/p62. This phenomenon can be reversed by the transfection of miR-221/222 inhibitors. These data suggested that miR-221/222 from HAoSMC-derived exosomes inhibited autophagy in HUVECs by modulating PTEN/Akt signaling pathway. [ABSTRACT FROM AUTHOR]