Estrogen induced changes in Akt-dependent activation of endothelial nitric oxide synthase and vasodilation
Estrogen induced changes in Akt-dependent activation of endothelial nitric oxide synthase and vasodilation
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DOI：
10.1016/j.steroids.2004.05.016
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发表时间：
2004-09-01
期刊：
影响因子：
2.7
通讯作者：
Magder, S
中科院分区：
文献类型：
--
作者：
Florian, M;Lu, Y;Magder, S
目的：雌激素急性给药导致血管舒张和一氧化氮（NO）产生增加。方法和结果：用17-β-雌二醇（E2）（10（-9）至10（-5）M）处理牛微血管和人脐内皮细胞（HUVEC）1分钟内增加Akt的磷酸化，随后是eNOS的磷酸化。这些作用可被PI（3）K抑制剂和Akt上游激活剂渥曼青霉素（wortmannin）阻断。雌激素受体拮抗剂ICI 182，780抑制eNOS磷酸化。E2增加钙依赖性NOS活性和亚硝酸盐的产生，这被渥曼青霉素和ICI 182，780抑制。E2可增加主动脉环对乙酰胆碱的舒张反应，wortmannin可阻断E2的这种作用。E2（10（-9）M）在无流量、恒流量和增加流量条件下扩张脑微血管，并被wortmannin阻断。雌激素受体部分拮抗剂三苯氧胺也能扩张微血管。结论：E2通过Akt/PKB依赖性途径增加NO的产生。这与对内皮依赖性扩张的敏感性增加有关。在脑微血管中，E2和他莫昔芬在低浓度下产生显著的扩张，有和没有乙酰胆碱诱导的内皮血管舒张刺激。(C)2004爱思唯尔公司All rights reserved.
Objectives: Acute administration of estrogen results in vasodilation and increased nitric oxide (NO) production. We examined the hypothesis that this is due to activation of Akt/PKB which subsequently increases eNOS activity.Methods and results: Treatment of bovine microvascular and human umbilical endothelial cells (HUVEC) with 17-beta-estradiol (E2) (10(-9) to 10(-5) M) increased phosphorylation of Akt within 1 min and this was followed by phosphorylation of eNOS. These effects were blocked by wortmannin, a PI(3)K inhibitor and the upstream activator of Akt. The estrogen receptor antagonist, ICI 182,780, inhibited eNOS phosphorylation. E2 increased calcium dependent NOS activity and nitrite production and this was inhibited by wortmannin and ICI 182,780. E2 increased the vasodilatory response of aortic rings to acetylcholine and wortmannin blocked the effect. E2 (10(-9) M) dilated cerebral microvascular vessels under conditions of no flow, constant flow and increasing flow and this was blocked by wortmannin. Tamoxifen, a partial estrogen receptor antagonist, also dilated the microvessels.Conclusions: E2 increases NO production through an Akt/PKB dependent pathway. This is associated with increased sensitivity to endothelial dependent dilation. In cerebral microvessels, E2 and tamoxifen produce significant dilation at low concentrations with and without acetylcholine induced stimulation of endothelial vasodilation. (C) 2004 Elsevier Inc. All rights reserved.