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The aim of the present study was to identify whether sepsis-induced vascular hyporeactivity is associated with microcirculation disturbance and multiple organ injuries. The current study assessed the impact of resveratrol (Res) treatment on lipopolysaccharide (LPS) challenge mediated vascular hyporeactivity. Effects of Res treatment (30 mg/kg; i.m.) at 1 h following LPS stimulation (5 mg/kg; i.v.) on the survival time, mean arterial pressure (MAP), and maximal difference of MAP (ΔMAP) to norepinephrine (NE; 4.2 µg/kg) in mice were observed. The reactivity to gradient NE of isolated mesenteric arterioles and the association with the RhoA-RhoA kinase (ROCK)-myosin light chain phosphatase (MLCP) pathway were investigated by myography, and the signaling molecule protein levels were assessed using ELISA. Res treatment prolonged the survival time of mice subjected to LPS challenge, but did not prevent the LPS-induced hypotension and increase in ΔMAP. Res treatment and RhoA agonist U-46619 incubation prevented LPS-induced vascular hyporeactivity ex vivo, which were suppressed by incubation with ROCK inhibitor Y-27632. LPS-induced vascular hyporeactivity was not affected by the MLCP inhibitor okadaic acid incubation, but was further downregulated by the co-incubation of OA plus Y-27632. The inhibiting effect of Y-27632 on Res treatment was eradicated by incubation with U-46619. Furthermore, RhoA inhibitor C3 transferase did not significantly inhibit the enhancing role of Res treatment, which was further increased by U-46619 plus C3 transferase co-incubation. In addition, Res treatment eradicated the LPS-induced decreases in p-RhoA and p-Mypt1 levels and increases in MLCP levels. The results of the present study indicate that post-treatment of Res significantly ameliorates LPS-induced vascular hyporeactivity, which is associated with the activation of the RhoA-ROCK-MLCP pathway.