Department of Pharmacology, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
J Pharm Pharmacol. 2013 Oct;65(10):1488-99. doi: 10.1111/jphp.12113. Epub 2013 Aug 6.
The G protein-coupled oestrogen receptor-1 (GPER-1) agonist G1 induces endothelium-dependent relaxation. Activation of the epidermal growth factor (EGF) receptor leads to transduction of signals from the plasma membrane for the release of nitric oxide. We tested the hypothesis that G1 induces endothelium-dependent vasorelaxation through activation of the EGF receptor.
Rat aortic rings were mounted in organ baths. After pretreatment with various inhibitors, aortic rings contracted with 11,9-epoxymethano-prostaglandin F2α or KCl were subjected to relaxation by G1.
G1 induced endothelium-dependent vasorelaxation, which was attenuated by pretreatment with either L -N(ω) -nitroarginine methyl ester (L -NAME), an inhibitor of nitric oxide synthase, or (3aS,4R,9bR)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline HB-EGF, heparin-binding EGF-like growth factor, a GPER-1 antagonist. Neither a general oestrogen receptor antagonist, ICI 182 780, nor a selective oestrogen receptor-α antagonist, methyl-piperidino-pyrazole dihydrochloride (MPP), had an effect on G1-induced vasorelaxation. However, pretreatment with EGF receptor blockers, AG1478 or DAPH, resulted in attenuated G1-induced vasorelaxation. In addition, pretreatment with Src inhibitor 4-amino-3-(4-chlorophenyl)-1-(t-butyl)-1H-pyrazolo[3,4-d]pyrimidine, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine or Akt inhibitor VIII also resulted in attenuated vascular relaxation induced by the cumulative addition of G1. However, neither phosphatidylinositol-3 kinase inhibitors LY294002 and wortmannin nor an extracellular signal-regulated kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto) butadiene monoethanolate had effect on vascular relaxation induced by the cumulative addition of G1.
G1 induces endothelium-dependent vasorelaxation through Src-mediated activation of the EGF receptor and the Akt pathway in rat aorta.
G 蛋白偶联雌激素受体-1（GPER-1）激动剂 G1 诱导内皮依赖性舒张。表皮生长因子（EGF）受体的激活导致信号从质膜传递以释放一氧化氮。我们测试了 G1 通过激活 EGF 受体诱导内皮依赖性血管舒张的假说。
将大鼠主动脉环安装在器官浴中。用各种抑制剂预处理后，用 11,9-环氧甲氧基前列腺素 F2α或 KCl 收缩的主动脉环通过 G1 产生舒张反应。
G1 诱导内皮依赖性血管舒张，用一氧化氮合酶抑制剂 L-N（ω）-硝基精氨酸甲酯（L-NAME）或肝素结合表皮生长因子样生长因子（HB-EGF）预处理可减弱这种舒张作用，HB-EGF 是 GPER-1 拮抗剂。通用雌激素受体拮抗剂 ICI 182780 或选择性雌激素受体-α拮抗剂甲基哌啶基吡唑二盐酸盐（MPP）均对 G1 诱导的血管舒张无影响。然而，EGF 受体阻滞剂 AG1478 或 DAPH 的预处理导致 G1 诱导的血管舒张减弱。此外，Src 抑制剂 4-氨基-3-(4-氯苯基)-1-(叔丁基)-1H-吡唑并[3,4-d]嘧啶、4-氨基-5-(4-氯苯基)-7-(叔丁基)吡唑并[3,4-d]嘧啶或 Akt 抑制剂 VIII 的预处理也导致 G1 累积添加引起的血管舒张减弱。然而，磷脂酰肌醇-3 激酶抑制剂 LY294002 和渥曼青霉素以及细胞外信号调节激酶抑制剂 1,4-二氨基-2,3-二氰基-1,4-双（o-氨基苯巯基）丁二烯单乙醇胺对 G1 累积添加引起的血管舒张均无影响。
G1 通过Src 介导的 EGF 受体和 Akt 通路激活诱导大鼠主动脉内皮依赖性血管舒张。
