Supplemental Digital Content is available in the text. Previously, we showed that peripheral administration of 2-ME (2-methoxyestradiol), a CYP1B1 (cytochrome P450 1B1)-catechol-O-methyltransferase (COMT) generated metabolite of E2 (17β-Estradiol), protects against angiotensin II-induced hypertension in female mice. The demonstration that central E2 inhibits angiotensin II-induced hypertension, together with the expression of CYP1B1 in the brain, led us to hypothesize that E2-CYP1B1 generated metabolite 2-ME in the brain mediates its protective action against angiotensin II-induced hypertension in female mice. To test this hypothesis, we examined the effect of intracerebroventricularly (ICV) administered E2 in ovariectomized (OVX)-wild-type (Cyp1b1+/+) and OVX-Cyp1b1−/− mice on the action of systemic angiotensin II. ICV-E2 attenuated the angiotensin II-induced increase in mean arterial blood pressure, impairment of baroreflex sensitivity, and sympathetic activity in OVX-Cyp1b1+/+ but not in ICV-injected short interfering (si)RNA-COMT or OVX-Cyp1b1−/− mice. ICV-2-ME attenuated the angiotensin II-induced increase in blood pressure in OVX-Cyp1b1−/− mice; this effect was inhibited by ICV-siRNA estrogen receptor-α (ERα) and G protein-coupled estrogen receptor 1 (GPER1). ICV-E2 in OVX-Cyp1b1+/+ but not in OVX-Cyp1b1−/− mice and 2-ME in the OVX-Cyp1b1−/− inhibited angiotensin II-induced increase in reactive oxygen species production in the subfornical organ and paraventricular nucleus, activation of microglia and astrocyte, and neuroinflammation in paraventricular nucleus. Furthermore, central CYP1B1 gene disruption in Cyp1b1+/+ mice by ICV-adenovirus-GFP (green fluorescence protein)-CYP1B1-short hairpin (sh)RNA elevated, while reconstitution by adenovirus-GFP-CYP1B1-DNA in the paraventricular nucleus but not in subfornical organ in Cyp1b1−/− mice attenuated the angiotensin II-induced increase in systolic blood pressure. These data suggest that E2-CYP1B1-COMT generated metabolite 2-ME, most likely in the paraventricular nucleus via estrogen receptor-α and GPER1, protects against angiotensin II-induced hypertension and neuroinflammation in female mice.

中文翻译：

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中枢 CYP1B1（细胞色素 P450 1B1）-雌二醇代谢物 2-甲氧基雌二醇可预防雌性小鼠的高血压和神经炎症

补充数字内容在文本中可用。此前，我们表明外周给药 2-ME（2-甲氧基雌二醇），一种 CYP1B1（细胞色素 P450 1B1）-儿茶酚-O-甲基转移酶（COMT）产生的 E2（17β-雌二醇）代谢物，可预防血管紧张素 II 诱导的高血压在雌性小鼠中。中枢 E2 抑制血管紧张素 II 诱导的高血压的证明，连同大脑中 CYP1B1 的表达，使我们假设 E2-CYP1B1 在大脑中产生的代谢物 2-ME 介导其对血管紧张素 II 诱导的女性高血压的保护作用老鼠。为了验证这一假设，我们检查了脑室内 (ICV) 在去势 (OVX) 野生型 (Cyp1b1+/+) 和 OVX-Cyp1b1-/- 小鼠中施用 E2 对全身血管紧张素 II 作用的影响。在 OVX-Cyp1b1+/+ 中，ICV-E2 减弱了血管紧张素 II 诱导的平均动脉血压升高、压力反射敏感性受损和交感神经活动，但在注射 ICV 的短干扰 (si)RNA-COMT 或 OVX-Cyp1b1-/ 中没有减弱- 老鼠。ICV-2-ME 减弱了血管紧张素 II 诱导的 OVX-Cyp1b1-/- 小鼠血压升高；这种作用被 ICV-siRNA 雌激素受体-α (ERα) 和 G 蛋白偶联雌激素受体 1 (GPER1) 抑制。OVX-Cyp1b1+/+ 中的 ICV-E2 而不是 OVX-Cyp1b1−/− 小鼠中的 ICV-E2 和 OVX-Cyp1b1−/− 中的 2-ME 抑制了血管紧张素 II 诱导的穹窿下器官和室旁核中活性氧产生的增加，小胶质细胞和星形胶质细胞的激活，以及室旁核的神经炎症。此外，ICV-腺病毒-GFP（绿色荧光蛋白）-CYP1B1-短发夹（sh）RNA对Cyp1b1+/+小鼠中枢CYP1B1基因的破坏升高，而腺病毒-GFP-CYP1B1-DNA在室旁核重建，但不在穹窿下器官在 Cyp1b1-/- 小鼠中，血管紧张素 II 诱导的收缩压升高减弱。这些数据表明，E2-CYP1B1-COMT 产生的代谢物 2-ME，最有可能通过雌激素受体-α 和 GPER1 在室旁核中，保护雌性小鼠免受血管紧张素 II 诱导的高血压和神经炎症。