title: Formononetin upregulates nitric oxide synthase in arterial endothelium through estrogen receptors and MAPK pathways.
abstract: OBJECTIVE
  Formononetin, a phytoestrogen, can improve arterial endothelial cell function by upregulating endothelial nitric oxide synthase (eNOS). The estrogen receptor plays an important role in the regulation of eNOS. This study investigated the hypothesis that formononetin upregulates eNOS through estrogen receptors and MAPK pathways.
  
  
  METHODS
  The rat superior mesenteric arteries were cultured with formononetin or formononetin plus inhibitors for 24 h. The isometric tension of the arteries was measured using a myograph system. The mRNA and protein expression levels of eNOS were determined by real-time PCR and immunohistochemistry, respectively.
  
  
  RESULTS
  Acetylcholine (ACh) relaxed the mesenteric arteries precontracted with 5-hydroxytryptamine. This relaxation could be enhanced by formononetin. The removal of endothelium or incubation with l-NAME (a NOS inhibitor) completely abolished the formononetin-enhanced relaxation induced by ACh, suggesting that the formononetin-enhanced vasodilatation is dependent on endothelium and NO pathway. The estrogen receptor inhibitor ICI 182780 attenuated the formononetin-enhanced vasodilatation induced by ACh, suggesting that the formononetin-enhanced arterial relaxation is mediated by the estrogen receptor. Formononetin increased the mRNA and protein expression levels of eNOS. ICI 182780, U0126 (an ERK1/2 inhibitor) and SP600125 (a JNK inhibitor) prevented the increases in arterial relaxation and eNOS levels.
  
  
  CONCLUSIONS
  Formononetin upregulates eNOS expression in mesenteric arteries via estrogen receptors, ERK1/2 and JNK pathways.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.|Department of Pharmaceutics, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Ping
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
authors.forename: Dong-Zheng
authors.initials: DZ
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
authors.forename: Yong-Xiao
authors.initials: YX
authors.lastname: Cao
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D007529:Isoflavones; D011960:Receptors, Estrogen; C007768:formononetin; D012701:Serotonin; D052250:Nitric Oxide Synthase Type III; D020928:Mitogen-Activated Protein Kinases; D000109:Acetylcholine
keywords: endothelial nitric oxide synthase; estrogen receptor; formononetin; mesenteric artery; mitogen-activated protein kinase pathway; rat