Kuhlmann Michael T, Cuhlmann Simon, Hoppe Irmgard, Krams Rob, Evans Paul C, Strijkers Gustav J, Nicolay Klaas, Hermann Sven, Schäfers Michael
European Institute for Molecular Imaging, Westfälische Wilhelms-University Münster, Germany.
J Vis Exp. 2012 Jan 13(59):3308. doi: 10.3791/3308.
It is widely accepted that alterations in vascular shear stress trigger the expression of inflammatory genes in endothelial cells and thereby induce atherosclerosis (reviewed in (1) and (2)). The role of shear stress has been extensively studied in vitro investigating the influence of flow dynamics on cultured endothelial cells and in vivo in larger animals and humans. However, highly reproducible small animal models allowing systematic investigation of the influence of shear stress on plaque development are rare. Recently, Nam et al. introduced a mouse model in which the ligation of branches of the carotid artery creates a region of low and oscillatory flow. Although this model causes endothelial dysfunction and rapid formation of atherosclerotic lesions in hyperlipidemic mice, it cannot be excluded that the observed inflammatory response is, at least in part, a consequence of endothelial and/or vessel damage due to ligation. In order to avoid such limitations, a shear stress modifying cuff has been developed based upon calculated fluid dynamics, whose cone shaped inner lumen was selected to create defined regions of low, high and oscillatory shear stress within the common carotid artery. By applying this model in Apolipoprotein E (ApoE) knockout mice fed a high cholesterol western type diet, vascular lesions develop upstream and downstream from the cuff. Their phenotype is correlated with the regional flow dynamics as confirmed by in vivo Magnetic Resonance Imaging (MRI): Low and laminar shear stress upstream of the cuff causes the formation of extensive plaques of a more vulnerable phenotype, whereas oscillatory shear stress downstream of the cuff induces stable atherosclerotic lesions. In those regions of high shear stress and high laminar flow within the cuff, typically no atherosclerotic plaques are observed. In conclusion, the shear stress-modifying cuff procedure is a reliable surgical approach to produce phenotypically different atherosclerotic lesions in ApoE-deficient mice.
人们普遍认为，血管剪切应力的改变会触发内皮细胞中炎症基因的表达，从而诱发动脉粥样硬化（详见参考文献(1)和(2)）。剪切应力的作用已在体外进行了广泛研究，探讨流动动力学对培养的内皮细胞的影响，也在大型动物和人类体内进行了研究。然而，能够系统研究剪切应力对斑块形成影响的高度可重复的小动物模型却很少见。最近，Nam等人引入了一种小鼠模型，其中结扎颈动脉分支会形成一个低流量和振荡流区域。尽管该模型会导致高脂血症小鼠出现内皮功能障碍和动脉粥样硬化病变的快速形成，但不能排除观察到的炎症反应至少部分是由于结扎导致的内皮和/或血管损伤的结果。为了避免此类局限性，基于计算流体动力学开发了一种剪切应力调节袖带，其锥形内腔被设计用于在颈总动脉内创建低、高和振荡剪切应力的特定区域。通过将该模型应用于喂食高胆固醇西式饮食的载脂蛋白E（ApoE）基因敲除小鼠，血管病变在袖带的上游和下游形成。它们的表型与区域流动动力学相关，这已通过体内磁共振成像（MRI）得到证实：袖带上游的低剪切应力和层流会导致形成更易损表型的广泛斑块，而袖带下游的振荡剪切应力会诱导稳定的动脉粥样硬化病变。在袖带内高剪切应力和高 laminar 流的那些区域，通常未观察到动脉粥样硬化斑块。总之，剪切应力调节袖带手术是一种可靠的手术方法，可在ApoE缺陷小鼠中产生表型不同的动脉粥样硬化病变。
