Age-associated impairment in vasorelaxation to fluid shear stress in the female vasculature is improved by TNF-α antagonism
Age-associated impairment in vasorelaxation to fluid shear stress in the female vasculature is improved by TNF-α antagonism
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DOI：
10.1152/ajpheart.00990.2005
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发表时间：
2006-03-01
影响因子：
4.8
通讯作者：
Davidge, ST
中科院分区：
文献类型：
--
作者：
Arenas, IA;Xu, Y;Davidge, ST
衰老与血管动态平衡的改变有关，包括血流介导的血管扩张减少，这在女性中与更年期的开始有关。我们之前发现，在雌性动物中，衰老与肿瘤坏死因子-α的增加有关。因此，我们研究了体内肿瘤坏死因子-α抑制老年雌性大鼠血管对剪切力反应的作用。用安慰剂或肿瘤坏死因子-α抑制剂(依那西普，0.3 mg/kg)处理接近生殖衰老的幼鼠(3mo)和去卵巢SD雌性大鼠(12mo)，分离肠系膜动脉(约150微米)，置于加压肌图仪上。血管在60毫米汞柱的腔内压力下平衡，然后用苯肾上腺素以类似于其初始直径的70%的速度预收缩。灌流液流量从0增加到150亩L/分钟。与年轻血管相比，老年血管的血流介导性扩张降低[最大扩张(均值+/-SE)：52+/-4vs.24+/-15%；P<；0.05]，这可通过抑制肿瘤坏死因子-α而得到改善。此外，在老年血管中，与年轻血管相比，最大的血流扩张是在较高的切应力水平上。在所有组中，通过去除内皮细胞或用N-G-硝基-L-精氨酸甲酯抑制一氧化氮合酶来取消血流介导的扩张。然而，N-G-硝基-L-精氨酸甲酯对老年动物血管的调节作用较年轻动物减弱，但在依那西普治疗的老年动物中得到改善。体内慢性抑制肿瘤坏死因子-α改善老年雌性动物阻力动脉的血流介导的动脉扩张。
Aging is associated with alterations in vascular homeostasis, including a reduction in flow-mediated vasodilation, which in women is related to the onset of menopause. We previously found that in female animals, aging is associated with an increase in TNF-alpha. Thus we investigated the role of in vivo TNF-alpha inhibition on vascular responses to shear stress in aging female rats. Mesenteric arteries (similar to 150 mu m) were isolated from young (3 mo) and ovariectomized Sprague-Dawley female rats approaching reproductive senescence (12 mo) treated with either placebo or a TNF-alpha inhibitor (etanercept; 0.3 mg/kg) and were mounted on a pressure myograph system. Vessels were equilibrated at an intraluminal pressure of 60 mmHg and then preconstricted with phenylephrine at similar to 70% of their initial diameter. Perfusate flow was increased in steps from 0 to 150 mu l/min. Compared with young vessels, aged vessels have a decrease in flow-mediated dilation [maximal dilation (means +/- SE): 52 +/- 4 vs. 24 +/- 15%; P < 0.05], which was improved by TNF-alpha inhibition. Moreover, in aged vessels maximal dilation to flow was achieved at higher levels of shear stress compared with young vessels. In all groups, flow-mediated dilation was abolished by either endothelial removal or nitric oxide synthase inhibition with N-G-nitro-L-arginine methyl ester. However, the modulation by N-G-nitro-L-arginine methyl ester was reduced in vessels from aged animals compared with young animals but was improved in the etanercept- treated aged animals. In vivo chronic TNF-alpha inhibition improves flow-mediated arterial dilation in resistance arteries of aged female animals.