Introduction: Shear-sensitive micro-RNAs play an integral role in dictating vascular wall pro-inflammatory response and development of atherosclerosis. Previously, our group and others have identified an inverse relationship between micro-RNA-155 (miR-155) expression and inflammation in atheroprone areas of chronic low magnitude oscillatory shear stress (OSS) in vasculature and in-vitro. Hypothesis: we hypothesized that miR-155 negatively regulates acute OSS-induced vascular inflammation and dysfunction, via modulation of the MAPK-ETS-1 pathway. Methods: 12-week old C57B/6J wild type (WT) and miR-155 knockout mice (KO) were subjected to abdominal aortic coarctation (AAC), a unique model of acute induction of OSS, for 3-7 days. Downstream acute OSS segments were compared to upstream unidirectional shear stress (USS) segments of thoracic aorta using RT-PCR, western blot and two-way ANOVA followed by Tukey’s multiple comparison analyses. Results: In WT mice, acute OSS induced vascular inflammation evidenced by upregulation of MCP-1 and VCAM-1 expression in OSS segments compared with USS. This was associated with loss of vascular barrier function as evaluated by extravasation of Evans-blue dye assay along with increased MMP-9 and MMP-3 expression. However, vascular miR-155 levels were also higher in OSS segments compared with USS (n=6-12, P<0.05). Nevertheless, miR-155 KO mice showed enhanced expression and activation of ERK and p-38 MAPKs and downstream ETS-1, VCAM-1 and MMP-9 expression in OSS segments compared with USS versus WT controls (n=3-4, P<0.05). Tail vein injections of miR-155 overexpressing lentivirus particles in WT mice after AAC resulted in further upregulation of miR-155 and abolished OSS-induced upregulation of p-38 and downstream ETS-1, VCAM-1 and MMP-9 expression in OSS segments compared with USS versus scramble controls (n=5-6, P<0.05). Conclusions: Despite the early upregulation of shear-sensitive miR-155, our data suggest that miR-155 serves as a negative feedback regulator to acute OSS-induced vascular inflammation via inhibition of p-38 and ETS-1. Further studies are in progress to evaluate the effect of exogenous miR-155 on OSS-induced oxidative stress and vascular function, which can serve as basis for developing novel miRNA-based therapeutic modalities.