Dihydrotestosterone stimulates cerebrovascular inflammation through NFkappaB, modulating contractile function.
Dihydrotestosterone stimulates cerebrovascular inflammation through NFkappaB, modulating contractile function.
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DOI：
10.1038/jcbfm.2008.115
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发表时间：
2009-02
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--
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我们之前的研究表明，长期睾酮治疗会增强生理条件下的血管张力，并加剧内毒素引起的脑循环炎症。然而，睾酮可以通过芳香酶代谢为雌激素，从而引起雄激素和雌激素作用之间的平衡。因此，我们研究了不可芳香化雄激素受体激动剂二氢睾酮 (DHT) 对脑血管炎症 NFκB 通路的影响。从体内长期接受 DHT 治疗的睾丸切除雄性大鼠中分离出脑动脉。或者，从睾丸切除的男性中分离软脑膜动脉，并将其离体暴露于培养基中的DHT或媒介物。体内或离体 DHT 治疗可增加脑动脉中核 NFκB 的激活，并增加 NFκB 激活的促炎产物环加氧酶 2 (COX-2) 和诱导型 NO 合酶 (iNOS) 的水平。氟他胺减弱了 DHT 对 COX-2 和 iNOS 的影响。在经 DHT 处理的大鼠分离的受压大脑中动脉中，选择性 COX-2 抑制剂 NS398 或选择性 iNOS 抑制剂 L-nil 的收缩增加，证实了 DHT 暴露的功能性后果。总之，选择性雄激素受体激动剂 DHT 激活 NFκB 介导的 COX-2/iNOS 通路，导致血管炎症状态。这种效应可能导致脑血管病理生理学中性别相关的差异。
Our previous studies demonstrate that chronic testosterone treatment augments vascular tone under physiological conditions and exacerbates endotoxin-induced inflammation in the cerebral circulation. However, testosterone can be metabolized by aromatase to estrogen, evoking a balance between androgenic and estrogenic effects. Therefore, we investigated the effect of the non-aromatizable androgen receptor agonist, dihydrotestosterone (DHT), on the inflammatory NFκB pathway in cerebral blood vessels. Cerebral arteries were isolated from orchiectomized male rats treated chronically with DHT in vivo. Alternatively, pial arteries were isolated from orchiectomized males and were exposed ex vivo to DHT or vehicle in culture medium. DHT treatment, in vivo or ex vivo, increased nuclear NFκB activation in cerebral arteries and increased levels of the proinflammatory products of NFκB activation, cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS). Effects of DHT on COX-2 and iNOS were attenuated by flutamide. In isolated pressurized middle cerebral arteries from DHT-treated rats constrictions to the selective COX-2 inhibitor NS398 or the selective iNOS inhibitor L-nil were increased, confirming a functional consequence of DHT exposure. In conclusion, activation of the NFκB mediated COX-2/iNOS pathway by the selective androgen receptor agonist, DHT, results in a state of vascular inflammation. This effect may contribute to sex-related differences in cerebrovascular pathophysiology.
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影响因子：
2.9
作者：
Hawk, T;Zhang, YQ;Simpkins, JW
通讯作者：
Simpkins, JW
DOI：
10.1152/ajpheart.2000.279.2.h610
发表时间：
2000-08-01
影响因子：
4.8
作者：
Geary, GG;Krause, DN;Duckles, SP
通讯作者：
Duckles, SP
DOI：
10.1152/ajpheart.00465.2005
发表时间：
2005-11-01
影响因子：
4.8
作者：
Razmara, A;Krause, DN;Duckles, SP
通讯作者：
Duckles, SP
影响因子：
5.8
作者：
Norata, GD;Tibolla, G;Catapano, AL
通讯作者：
Catapano, AL
影响因子：
--
作者：
McKay, LI;Cidlowski, JA
通讯作者：
Cidlowski, JA