探讨表达APP-C100和SOD_1基因突变子的转基因小鼠血管反应性变化的机制

A study on the mechanism of alterations in vascular reactivity in single-and double-transgenic mice coexpressing human APP-C100 and mutant SOD_1 gene

目的探讨转单基因和转双基因小鼠外周微血管反应性改变的作用机制。方法在未转基因、转单基因和转双基因小鼠的后足爪垫皮肤暴露微血管网,灌注血管扩张剂乙酰胆碱和硝普钠,多普勒检测血液流量变化,应用Westernblot检测小鼠血中β淀粉样蛋白(Aβ)水平。结果与未转基因和转单基因(表达SOD1基因突变子G93A)小鼠相比,2～3个月龄转单基因(表达APPC100、TgC100)和转双基因(APPC100和SOD1基因突变子G93A基因共表达)小鼠外周血液流量下降28%,8～9个月龄TgC100小鼠外周血液流量减少34%,TgC100和转双基因小鼠外周血Aβ水平较未转基因小鼠明显升高(P<0.01)。结论TgC100和转双基因小鼠外周血管反应性的改变很可能由循环性可溶性Aβ引起,Aβ血管活性涉及内皮和非内皮机制。

Objective To explore the mechanism underlying the changes of microvascular reactivity in single and double transgenic mice.Methods Peripheral vascular reactivity to vasodilators acetylcholine and sodium nitroprusside on perfused microvasculature of the hind footpads was investigated using nontransgenic,single transgenic mice expressing human APP-C100(TgC100.WT or TgC100.V717F)and double transgenic mice coexpressing human APP-C100 and human SOD 1(G93A) genes.Results Single APP-C100 and double Tg mice C100/SOD 1(G93A) at 2-3 months old showed a statistical decrease of 28% in blood flux compared to that in nontransgenic control mice.In addition,the vasodilative responsiveness was markedly reduced by 34% in 8-9 months old TgC100 mice compared to that in control mice.On the other hand,there was no significant difference in the profile of vasodilative reaction between TgC100.WT and TgC100.V717F mice.TgC100 and double Tg mice also contained higher levels of Aβ peptide in plasma than nontransgenic mice(P<0.01). Conclusion The altered reactivity of microvasculature may be mediated by circulating soluble Aβ peptides.The mechanisms underlying vasoactivity of circulating Aβ in TgC100 and double Tg mice may involve the endothelium and nonendothelium.