Mori Yusaku, Gonzalez Medina Marel, Liu Zhiwei, Guo June, Dingwell Luke S, Chiang Simon, Kahn Carl Ronald, Husain Mansoor, Giacca Adria
Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Division of Diabetes, Metabolism, and Endocrinology, Anti-Glycation Research Section, Department of Medicine, Showa University School of Medicine, Shinagawa, Tokyo, Japan.
Diab Vasc Dis Res. 2021 May-Jun;18(3):14791641211027324. doi: 10.1177/14791641211027324.
Insulin exerts vasculoprotective effects on endothelial cells (ECs) and growth-promoting effects on vascular smooth muscle cells (SMCs) in vitro, and suppresses neointimal growth in vivo. Here we determined the role of ECs and SMCs in the effect of insulin on neointimal growth.
Mice with transgene CreER under the control of EC-specific Tie2 (Tie2-Cre) or SMC-specific smooth muscle myosin heavy chain promoter/enhancer (SMMHC-Cre) or littermate controls were crossbred with mice carrying a loxP-flanked insulin receptor (IR) gene. After CreER-loxP-mediated recombination was induced by tamoxifen injection, mice received insulin pellet or sham (control) implantation, and underwent femoral artery wire injury. Femoral arteries were collected for morphological analysis 28 days after wire injury.
Tamoxifen-treated mice showed lower IR expression in ECs, but not in SMCs, than mice. Insulin treatment reduced neointimal area after arterial injury in mice, but had no effect in mice. Tamoxifen-treated mice showed lower IR expression in SMCs, but not in ECs, than mice. Insulin treatment reduced neointimal area in mice, whereas unexpectedly, it failed to inhibit neointima formation in mice.
Insulin action in both ECs and SMCs is required for the "anti-restenotic" effect of insulin in vivo.
胰岛素在体外对内皮细胞（ECs）具有血管保护作用，对血管平滑肌细胞（SMCs）具有促生长作用，并在体内抑制新生内膜生长。在此，我们确定了ECs和SMCs在胰岛素对新生内膜生长影响中的作用。
将内皮细胞特异性Tie2（Tie2-Cre）或平滑肌细胞特异性平滑肌肌球蛋白重链启动子/增强子（SMMHC-Cre）控制下的转基因CreER小鼠或同窝对照与携带loxP侧翼胰岛素受体（IR）基因的小鼠杂交。通过注射他莫昔芬诱导CreER-loxP介导的重组后，小鼠接受胰岛素植入物或假手术（对照）植入，并进行股动脉钢丝损伤。钢丝损伤28天后收集股动脉进行形态学分析。
与未处理小鼠相比，他莫昔芬处理的小鼠ECs中IR表达较低，但SMCs中无此现象。胰岛素处理可减少未处理小鼠动脉损伤后的新生内膜面积，但对处理小鼠无影响。与未处理小鼠相比，他莫昔芬处理的小鼠SMCs中IR表达较低，但ECs中无此现象。胰岛素处理可减少未处理小鼠的新生内膜面积，但出乎意料的是，它未能抑制处理小鼠的新生内膜形成。
胰岛素在体内的“抗再狭窄”作用需要ECs和SMCs中的胰岛素作用共同参与。
