BACKGROUND Previously, we showed that 6β-hydroxytestosterone (6β-OHT), a cytochrome P450 1B1 (CYP1B1)-derived metabolite of testosterone, contributes to angiotensin II (Ang II)-induced hypertension in male mice. This study was conducted to test the hypothesis that 6β-OHT contributes to increased vascular reactivity, endothelial dysfunction, vascular hypertrophy, and reactive oxygen species production associated with Ang II-induced hypertension. METHODS Eight- to 10-week-old intact or castrated C57BL/6 J (Cyp1b1+/+ and Cyp1b1-/-) mice were anesthetized for implantation of a micro-osmotic pump which delivered Ang II (700 ng/kg/day) or saline for 14 days. Mice were injected with 6β-OHT (15 μg/g b.w every third day), flutamide (8 mg/kg every day), or its vehicle. Blood pressure was measured via tail-cuff. Vascular reactivity, endothelial-dependent and endothelial-independent vasodilation, media to lumen ratio, fibrosis by collagen deposition, and reactive oxygen species production by dihydroethidium staining were determined in the isolated thoracic aorta. RESULTS The response of thoracic aorta to phenylephrine and endothelin-1 was increased in Ang II-infused Cyp1b1+/+ mice compared to intact Cyp1b1-/- or castrated Cyp1b1+/+ and Cyp1b1-/- mice; these effects of Ang II were restored by treatment with 6β-OHT. Ang II infusion caused endothelial dysfunction, as indicated by decreased relaxation of the aorta to acetylcholine in Cyp1b1+/+ but not Cyp1b1-/- or castrated Cyp1b1+/+ and Cyp1b1-/- mice. 6β-OHT did not alter Ang II-induced endothelial dysfunction in Cyp1b1+/+ mice but restored it in Cyp1b1-/- or castrated Cyp1b1+/+ and Cyp1b1-/- mice. Ang II infusion increased media to lumen ratio and caused fibrosis and reactive oxygen species production in the aorta of Cyp1b1+/+ mice. These effects were minimized in the aorta of Cyp1b1-/- or castrated Cyp1b1+/+ and Cyp1b1-/- mice and restored by treatment with 6β-OHT. Treatment with the androgen receptor antagonist flutamide reduced blood pressure and vascular hypertrophy in castrated Ang II-infused mice injected with 6β-OHT. CONCLUSIONS 6β-OHT is required for the action of Ang II to increase vascular reactivity and cause endothelial dysfunction, hypertrophy, and increase in oxygen radical production. The effect of 6β-OHT in mediating Ang II-induced hypertension and associated hypertrophy is dependent on the androgen receptor. Therefore, CYP1B1 could serve as a novel target for the development of therapeutics to treat vascular changes in hypertensive males.

中文翻译：

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CYP1B1产生的睾丸激素代谢产物6β-羟睾丸激素有助于血管紧张素II诱导的雄性小鼠高血压的血管变化。

背景技术以前，我们显示了细胞色素P450 1B1（CYP1B1）衍生的睾丸激素代谢物6β-羟基睾丸激素（6β-OHT）有助于血管紧张素II（Ang II）诱导的雄性小鼠高血压。进行这项研究以检验6β-OHT有助于与Ang II诱发的高血压相关的血管反应性，内皮功能障碍，血管肥大和活性氧生成的假设。方法将八至十周大的完整或去势的C57BL / 6 J（Cyp1b1 + / +和Cyp1b1-/-）小鼠麻醉，植入微渗透泵，该泵输送Ang II（700 ng / kg / day）或生理盐水14天。给小鼠注射6β-OHT（每三天15μg/ g体重），氟他胺（每天8 mg / kg）或其媒介物。通过尾袖带测量血压。血管反应性 在分离的胸主动脉中测定内皮依赖性和内皮依赖性血管舒张，介质与管腔的比率，胶原沉积引起的纤维化以及二氢乙啶染色产生的活性氧。结果与完整的Cyp1b1-/-或去势的Cyp1b1 + / +和Cyp1b1-/-小鼠相比，注入Ang II的Cyp1b1 + / +小鼠胸主动脉对苯肾上腺素和内皮素-1的反应增加；Ang II的这些作用通过6β-OHT的治疗得以恢复。Ang II输注引起内皮功能障碍，如Cyp1b1 + / +中主动脉对乙酰胆碱的舒张减少，但Cyp1b1-/-或cast割的Cyp1b1 + / +和Cyp1b1-/-小鼠则不然。6β-OHT不会改变Ang II诱导的Cyp1b1 + / +小鼠的内皮功能障碍，但可以在Cyp1b1-/-或去势的Cyp1b1 + / +和Cyp1b1-/-小鼠中恢复。Ang II输注会增加Cyp1b1 + / +小鼠主动脉的介质与管腔比率，并导致纤维化和活性氧的产生。这些作用在Cyp1b1-/-或去势的Cyp1b1 + / +和Cyp1b1-/-小鼠的主动脉中减至最小，并通过6β-OHT处理得以恢复。用雄激素受体拮抗剂氟他胺治疗可降低注射6β-OHT的去势的Ang II输注小鼠的血压和血管肥大。结论6β-OHT是Ang II增加血管反应性并引起内皮功能障碍，肥大和增加氧自由基产生的作用所必需的。6β-OHT在介导Ang II诱导的高血压和相关肥大中的作用取决于雄激素受体。因此，