Department of Physiology, University of Valencia, Valencia, Spain.
Exp Gerontol. 2010 Nov;45(11):868-74. doi: 10.1016/j.exger.2010.07.007. Epub 2010 Aug 12.
The aim of this work was to characterize a mouse model of experimental menopause and cardiovascular aging that closely reflects menopause in women. Senescence accelerated mouse (SAM)-Resistant type 1 (SAMR1, n=30) and SAM-Prone type 8 (SAMP8, n=30) were separated at 5months of age into three groups: 1) sham-operated (Sham); 2) ovariectomized (Ovx); and 3) ovariectomized chronically-treated with estrogen (Ovx+E2). Contractile responses to KCl (60mM) and thromboxane A(2) were greater in aorta from SAMP8 mice compared with SAMR1 in all groups. Neither ovariectomy nor estrogen replacement modified the contractile responses from SAMR1 mice. Conversely, in Ovx SAMP8 the increased maximal contractions were reversed by estrogen treatment. Rings with endothelium from all SAMR1 groups showed a greater relaxation to acetylcholine than SAMP8 groups. In SAMR1, endothelium-dependent relaxation was not altered in Ovx or Ovx+E2 groups. Rings from Ovx SAMP8 showed a decreased maximal response to acetylcholine compared to Sham SAMP8. Estrogen replacement restored the response to acetylcholine altered by ovariectomy. Nitric oxide inhibition by L-NAME markedly reduced acetylcholine responses in all groups, but this effect was less pronounced in SAMP8 and Ovx groups (determined by area under the curve reduction). These results indicate that SAMP8 exhibit a significant decreased endothelium-dependent and NO-mediated relaxation and increased vasoconstrictor responses that are potentiated by the lack of estrogen. Because these responses are closely in agreement with vascular dysfunction observed in menopausal women, we propose SAMP8 Ovx as a new model to concomitantly study the effects of aging and menopause in female mice.
本研究旨在建立一种能模拟人类绝经后心血管衰老的实验性绝经模型。将 5 月龄的衰老加速敏感 1 型（SAMR1）和衰老加速抵抗 8 型（SAMP8）小鼠分为假手术（Sham）组、去卵巢（Ovx）组和去卵巢后给予雌激素（Ovx+E2）治疗组，每组 10 只。结果显示：与 SAMR1 组相比，SAMP8 组的主动脉对 KCl（60mM）和血栓素 A2 的收缩反应更强。去卵巢或给予雌激素替代均未改变 SAMR1 组的收缩反应。相反，在 Ovx SAMP8 中，雌激素治疗逆转了最大收缩增加。所有 SAMR1 组的血管环对乙酰胆碱的舒张反应均大于 SAMP8 组。SAMR1 组去卵巢或 Ovx+E2 处理均不改变内皮依赖性舒张。与 Sham SAMP8 相比，Ovx SAMP8 组的血管环对乙酰胆碱的最大反应降低。雌激素替代恢复了 Ovx 改变的乙酰胆碱反应。L-NAME 抑制一氧化氮显著降低了所有组的乙酰胆碱反应，但在 SAMP8 和 Ovx 组中的效果较弱（通过曲线下面积减少来确定）。这些结果表明，SAMP8 表现出明显的内皮依赖性和 NO 介导的舒张减少以及血管收缩反应增强，而雌激素缺乏会增强这些反应。由于这些反应与绝经后女性观察到的血管功能障碍非常吻合，我们提出 SAMP8 Ovx 作为一种新的模型，可同时研究雌性小鼠衰老和绝经的影响。
