Testosterone augments endotoxin-mediated cerebrovascular inflammation in male rats
Testosterone augments endotoxin-mediated cerebrovascular inflammation in male rats
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DOI：
10.1152/ajpheart.00465.2005
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发表时间：
2005-11-01
影响因子：
4.8
通讯作者：
Duckles, SP
中科院分区：
文献类型：
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作者：
Razmara, A;Krause, DN;Duckles, SP
炎症机制的激活有助于脑血管病理生理学。男性与中风风险增加有关，但对睾酮在脑循环中的作用知之甚少。因此，我们在体内和体外炎症模型中探索睾酮治疗对脑血管炎症的影响。我们假设睾酮会增加细胞炎症的两种血管标记物环氧化酶-2（考克斯-2）和诱导型一氧化氮合酶（iNOS）的表达。使用四组雄性大鼠[完整、睾丸切除（ORX）和用睾酮（ORXT）或睾酮代谢物17 β-雌二醇（ORXE）治疗的ORX]，我们确定了性激素对腹腔内注射LPS后脑血管炎症的影响。Western印迹分析显示，与完整或ORX大鼠相比，ORXT大鼠脑血管中炎症标志物的诱导增加。相反，在ORXE大鼠的脑血管中，内毒素诱导的考克斯-2和iNOS蛋白水平显著降低。ORXT大鼠脑血管的共聚焦显微镜显示，LPS处理后内皮细胞和平滑肌细胞中的考克斯-2和iNOS免疫反应性增加。在与LPS体外孵育也诱导考克斯-2在软脑膜血管分离的四个动物治疗组，与ORX和ORXE组相比，在ORXT血管中观察到最大的诱导。从ORXT大鼠分离的脑血管中，PGE 2（一种主要的考克斯-2衍生的前列腺素终产物）的产生也最大。总之，睾酮增加脑血管炎症;这种影响可能有助于男性和女性之间的中风差异。
Activation of inflammatory mechanisms contributes to cerebrovascular pathophysiology. Male gender is associated with increased stroke risk, yet little is known about the effects of testosterone in the cerebral circulation. Therefore, we explored the impact of testosterone treatment on cerebrovascular inflammation with both in vivo and in vitro models of inflammation. We hypothesized that testosterone would augment the expression of two vascular markers of cellular inflammation, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Using four groups of male rats [intact, orchiectomized (ORX), and ORX treated with either testosterone (ORXT) or the testosterone metabolite 17 beta-estradiol (ORXE)], we determined effects of the sex hormones on cerebrovascular inflammation after intraperitoneal LPS injection. Western blot analysis showed that induction of inflammatory markers was increased in cerebral blood vessels from ORXT rats compared with intact or ORX rats. In contrast, in cerebral blood vessels from ORXE rats, there was a significant decrease in endotoxin-induced COX-2 and iNOS protein levels. Confocal microscopy of cerebral blood vessels from ORXT rats showed increased COX-2 and iNOS immunoreactivity in both endothelial and smooth muscle cells after LPS treatment. In vitro incubation with LPS also induced COX-2 in pial vessels isolated from the four animal treatment groups, with the greatest induction observed in ORXT vessels compared with the ORX and ORXE groups. Production of PGE2, a principal COX-2-derived prostaglandin end product, was also greatest in cerebral vessels isolated from ORXT rats. In conclusion, testosterone increases cerebrovascular inflammation; this effect may contribute to stroke differences between men and women.