Arenas Ivan A, Xu Yi, Davidge Sandra T
Perinatal Research Centre, Department of Obstetrics and Gynecology, 220 HMRC, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Am J Physiol Heart Circ Physiol. 2006 Mar;290(3):H1259-63. doi: 10.1152/ajpheart.00990.2005. Epub 2005 Nov 11.
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 (approximately 150 microm) 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 approximately 70% of their initial diameter. Perfusate flow was increased in steps from 0 to 150 microl/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.
衰老与血管稳态的改变有关，包括血流介导的血管舒张功能降低，在女性中这与绝经的开始有关。我们之前发现，在雌性动物中，衰老与肿瘤坏死因子-α（TNF-α）的增加有关。因此，我们研究了体内抑制TNF-α对衰老雌性大鼠血管对剪切应力反应的作用。从年轻（3个月）和接近生殖衰老（12个月）的去卵巢Sprague-Dawley雌性大鼠中分离出肠系膜动脉（约150微米），这些大鼠分别接受安慰剂或TNF-α抑制剂（依那西普；0.3毫克/千克）治疗，并安装在压力肌动描记系统上。血管在60毫米汞柱的腔内压力下平衡，然后用去氧肾上腺素预收缩至其初始直径的约70%。灌注液流量从0逐步增加到150微升/分钟。与年轻血管相比，衰老血管的血流介导的舒张功能降低[最大舒张（平均值±标准误）：52±4%对24±15%；P<0.05]，而TNF-α抑制可改善这种情况。此外，与年轻血管相比，衰老血管在更高的剪切应力水平下实现了对血流的最大舒张。在所有组中，通过去除内皮或用N(G)-硝基-L-精氨酸甲酯抑制一氧化氮合酶，血流介导的舒张功能均被消除。然而，与年轻动物相比，衰老动物血管中N(G)-硝基-L-精氨酸甲酯的调节作用降低，但在接受依那西普治疗的衰老动物中有所改善。体内慢性抑制TNF-α可改善衰老雌性动物阻力动脉中血流介导的动脉舒张。
