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Resveratrol Suppresses Sepsis-Induced Micro-vascular Hypo-reactivity Through Rac1-MLCK Pathway
Yang Yang1, Jun-Chao Liu2, Zhen-Kui Liu2
1Institute of Microcirculation & Basic Medical College, Hebei North University, Zhangjiakou, Hebei, China.
Introduction:
Vascular hyporeactivity contributes to a high mortality rate in sepsis. Resveratrol (Res) exhibits anti-inflammatory properties and improves vascular reactivity in septic animals. However, the mechanism of action of Res in sepsis-induced vascular hyporeactivity is not fully understood.
Methods:
A rat model of sepsis was established by intraperitoneal injection of fecal filtrate. Rats were divided into sham, sham + Res, sepsis, and sepsis + Res groups. Hemodynamic parameters, intestinal microcirculation (assessed by laser speckle contrast imaging and in vivo microcirculation imaging), and histopathological changes in intestinal and pulmonary tissues were evaluated. Vascular reactivity of isolated mesenteric micro-arteries was measured using a wire myograph system. The effects of serum from septic rats (SS) and Res-treated septic rats (SS-Res) on vascular smooth muscle cell viability and contractility were assessed in vitro. Protein expression of phosphorylated Ras-related C3 botulinum toxin substrate 1 and myosin light-chain kinase (p-MLCK) in vascular tissues were analyzed by western blotting. The roles of Ras-related C3 botulinum toxin substrate (Rac1) and MLCK were further verified using specific pharmacological activators and inhibitors.
Results:
Res improved the general health status, alleviated lung and intestinal injuries, and restored intestinal hemoperfusion and vessel distribution in SS. In addition, Res suppressed sepsis-induced intestinal microvascular hyporeactivity to norepinephrine in vitro, whereas treatment with Res-treated septic rats increased the cellular viability and contractility of vascular smooth muscle cells compared to SS. Furthermore, Res reversed the upregulated Ras-related C3 botulinum toxin substrate 1 and downregulated p-MLCK expressions in the mesenteric artery tissue of SS. The Rac1 activator platelet-derived growth factor and inhibitor NSC 27366 partially inhibited vascular reactivity in SS, whereas the effect of NSC 27366 was blocked by the MLCK inhibitor ML-7.
Conclusions:
Res suppressed sepsis-induced microvascular hyporeactivity through the Rac1-MLCK pathway, providing insights into the treatment of vascular hyporeactivity during sepsis.
