Actin-Binding Rho Activating Protein (Abra) Is Essential for Fluid Shear Stress-Induced Arteriogenesis
Actin-Binding Rho Activating Protein (Abra) Is Essential for Fluid Shear Stress-Induced Arteriogenesis
复制标题
DOI：
10.1161/atvbaha.109.195305
复制
发表时间：
2009-12-01
影响因子：
8.7
通讯作者：
Troidl, Christian
中科院分区：
文献类型：
--
作者：
Troidl, Kerstin;Rueding, Inka;Troidl, Christian
目的-动脉生成，即侧支循环的发展，对于组织存活很重要，但由于流体剪切应力（FSS）过早正常化，其功能仍然存在缺陷。使用慢性升高的 FSS 手术模型，我们发现兔子在股动脉结扎 (FAL) 后表现出正常的血流储备。 Fasudil 对 Rho 通路的抑制完全阻断了 FSS 的有益作用。在全基因组基因分析中，我们鉴定了肌动蛋白结合 Rho 激活蛋白 (Abra)，该蛋白在生长的侧枝中高度上调。方法和结果 - qRT-PCR 和蛋白质印迹证实了 Abra 在生长的侧枝中 FSS 依赖性表达高度增加。 L-NAME 的 NO 阻断消除了 FSS 生成的 Abra 表达以及整个动脉生成过程。细胞培养研究表明，Abra 通过需要 Rho 信号传导的机制触发平滑肌细胞增殖。与 FAL 后的自然反应相比，Abra 的局部侧支内腺病毒过度表达使兔子的侧支传导提高了 60%。相反，CL57BL/6小鼠中Abra的靶向缺失导致动脉生成受损。结论-动脉生成过程中FSS诱导的Abra表达由NO触发，并导致平滑肌细胞增殖刺激侧支生长。 （动脉硬化血栓 Vasc Biol.2009；29：2093-2101。）
Objective-Arteriogenesis, the development of a collateral circulation, is important for tissue survival but remains functionally defective because of early normalization of fluid shear stress (FSS). Using a surgical model of chronically elevated FSS we showed that rabbits exhibited normal blood flow reserve after femoral artery ligature (FAL). Inhibition of the Rho pathway by Fasudil completely blocked the beneficial effect of FSS. In a genome-wide gene profiling we identified actin-binding Rho activating protein (Abra), which was highly upregulated in growing collaterals.Methods and Results-qRT-PCR and Western blot confirmed highly increased FSS-dependent expression of Abra in growing collaterals. NO blockage by L-NAME abolished FSS-generated Abra expression as well as the whole arteriogenic process. Cell culture studies demonstrated an Abra-triggered proliferation of smooth muscle cells through a mechanism that requires Rho signaling. Local intracollateral adenoviral overexpression of Abra improved collateral conductance by 60% in rabbits compared to the natural response after FAL. In contrast, targeted deletion of Abra in CL57BL/6 mice led to impaired arteriogenesis.Conclusions-FSS-induced Abra expression during arteriogenesis is triggered by NO and leads to stimulation of collateral growth by smooth muscle cell proliferation. (Arterioscler Thromb Vasc Biol. 2009; 29:2093-2101.)