The acute estrogenic dilation of rat aorta is mediated solely by selective estrogen receptor-α agonists and is abolished by estrogen deprivation
The acute estrogenic dilation of rat aorta is mediated solely by selective estrogen receptor-α agonists and is abolished by estrogen deprivation
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DOI：
10.1124/jpet.104.082867
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发表时间：
2005-06-01
影响因子：
3.5
通讯作者：
Pinna, C
中科院分区：
文献类型：
--
作者：
Bolego, C;Cignarella, A;Pinna, C
已知雌激素可在离体动脉中诱导快速血管舒张反应。由于雌激素是一种非选择性受体激动剂，因此雌激素受体 (ER) 亚型在急性雌激素反应中的参与仍然难以捉摸。将选择性 ER α 激动剂 4,4', 4''-(4-丙基-[H-1]吡唑-1,3,5-三基)三苯酚 (PPT) 急性给药于完整雌性大鼠的预收缩主动脉环，剂量依赖性诱导 ER 依赖性血管舒张，与 17 β-雌二醇诱导的血管舒张完全重叠。相比之下，选择性 ER β 激动剂 2,3-双(4-羟基苯基)-丙腈 (DPN) 对血管舒缩没有急性影响。 PPT 的这种短期血管舒张作用被 NO 合酶抑制剂 N-omega-硝基-L-精氨酸甲酯和内皮去除所消除。然而，在卵巢切除 (OVX) 大鼠的主动脉组织中，17β-雌二醇和 PPT 均未诱导急性血管舒张。在雌激素替代的 OVX 大鼠的制剂中，PPT 的效果得以恢复，而 DPN 即使在雌激素替代后仍然无效。 PPT 通过 ER 依赖性机制发挥作用，如抗雌激素 ICI 182,780（7 α, 17 β-[9[(4,4,5,5,5-五氟戊基）亚磺酰基]壬基]estra-1,3,5(10)-triene-3,17-diol）存在时反应受损所示。因此，分离的大鼠主动脉内皮细胞表达ERα和ERβ。这些数据表明，选择性 ER α 而非 ER β 激动剂通过完整大鼠和 17 只 β-雌二醇替代的 OVX 大鼠的主动脉中受体介导的途径再现了雌激素的急性血管舒张。这种有益效果在 OVX 大鼠的组织中检测不到。因此，针对 ER 亚型的选择性药理学靶向可能代表了治疗血管疾病的一种新颖且有前途的方法。
Estrogen is known to induce rapid vasodilatory response in isolated arteries. Because estrogen is a nonselective receptor agonist, the involvement of estrogen receptor ( ER) subtypes in acute estrogenic responses has remained elusive. Acute administration of the selective ER alpha agonist 4,4', 4''-(4-propyl- [H-1] pyrazole- 1,3,5- triyl) tris-phenol (PPT) to precontracted aortic rings from intact female rats dose-dependently induced an ER-dependent vascular relaxation fully overlapping to that induced by 17 beta-estradiol. By contrast, the selective ER beta agonist 2,3- bis(4-hydroxyphenyl)- propionitrile (DPN) had no acute effect on vasomotion. This short-term vasorelaxant action of PPT was abolished by the NO synthase inhibitor N-omega-nitro-L-arginine methyl ester and by endothelium removal. In aortic tissues from ovariectomized (OVX) rats, however, neither 17 beta-estradiol nor PPT induced acute vascular relaxation. The effect of PPT was restored in preparations from estrogen-replaced OVX rats, whereas DPN remained ineffective even after estrogen replacement. PPT acted through an ER-dependent mechanism, as shown by impaired response in the presence of the anti-estrogen ICI 182,780 (7 alpha, 17 beta- [9[(4,4,5,5,5-pentafluoropentyl) sulfinyl] nonyl]estra-1,3,5(10)-triene-3,17-diol). Accordingly, isolated rat aortic endothelial cells expressed both ER alpha and ER beta. These data show that selective ER alpha but not ER beta agonists reproduced the acute vasodilation of estrogen via a receptor-mediated pathway in the aorta from intact as well as 17 beta-estradiol-replaced OVX rats. This beneficial effect was undetectable in tissues from OVX rats. Selective pharmacological targeting of ER subtypes may thus represent a novel and promising approach in the treatment of vascular disease.