Objective Dexmedetomidine(DEX),the most specificα^(2)-adrenergic receptor agonist widely used for its sedative and analgesic properties,has been reported to upregulate HIF-1αexpression to protect hypoxic and ischemi...Objective Dexmedetomidine(DEX),the most specificα^(2)-adrenergic receptor agonist widely used for its sedative and analgesic properties,has been reported to upregulate HIF-1αexpression to protect hypoxic and ischemic tissues.However,it is largely unclear whether DEX can also upregulate Hypoxiainducible factor-1 alpha(HIF-1α)expression and its downstream vascular endothelial growth factor-A(VEGFA)in cancer tissues with oxygen-deficient tumor microenvironment.Methods We used SMMC-7721 cells,MHCC97-H cells,and a mouse model of orthotopic hepatic carcinoma to explore the effect of DEX on angiogenesis and vasculogenic mimicry(VM)and its mechanism.Under normoxic(20%O^(2))and hypoxic(1%O^(2))conditions,DEX was used to intervene cells,and yohimbine was used to rescue them.Results The results showed that DEX promoted angiogenesis and VM in human liver cancer cells within a certain dose range,and the addition of yohimbine inhibited this effect.DEX could activate HIF-1α/VEGFA pathway,which was further verified by silencing HIF-1α.Consistently,in vivo results also showed that DEX can up-regulate HIF-1α/VEGFA expression,and enhance the number of VM channels and microvessel density(MVD).Conclusion We believe that HIF-1α/VEGFA might be an important signaling pathway by which DEX promotes angiogenesis and VM formation in human hepatocellular carcinoma,whereasα^(2)-adrenergic receptor mediation might be the critical mechanisms.展开更多
基金supported by the Natural Science Foundation of Zhejiang Province[LY19H160002]the Science and Technology Research Program of Jinhua City[2018-3-001b and 2017-3-020]
文摘Objective Dexmedetomidine(DEX),the most specificα^(2)-adrenergic receptor agonist widely used for its sedative and analgesic properties,has been reported to upregulate HIF-1αexpression to protect hypoxic and ischemic tissues.However,it is largely unclear whether DEX can also upregulate Hypoxiainducible factor-1 alpha(HIF-1α)expression and its downstream vascular endothelial growth factor-A(VEGFA)in cancer tissues with oxygen-deficient tumor microenvironment.Methods We used SMMC-7721 cells,MHCC97-H cells,and a mouse model of orthotopic hepatic carcinoma to explore the effect of DEX on angiogenesis and vasculogenic mimicry(VM)and its mechanism.Under normoxic(20%O^(2))and hypoxic(1%O^(2))conditions,DEX was used to intervene cells,and yohimbine was used to rescue them.Results The results showed that DEX promoted angiogenesis and VM in human liver cancer cells within a certain dose range,and the addition of yohimbine inhibited this effect.DEX could activate HIF-1α/VEGFA pathway,which was further verified by silencing HIF-1α.Consistently,in vivo results also showed that DEX can up-regulate HIF-1α/VEGFA expression,and enhance the number of VM channels and microvessel density(MVD).Conclusion We believe that HIF-1α/VEGFA might be an important signaling pathway by which DEX promotes angiogenesis and VM formation in human hepatocellular carcinoma,whereasα^(2)-adrenergic receptor mediation might be the critical mechanisms.
