Matrix-specific p21-activated kinase activation regulates vascular permeability in atherogenesis.
Matrix-specific p21-activated kinase activation regulates vascular permeability in atherogenesis.
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DOI：
10.1083/jcb.200609008
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发表时间：
2007-02-26
影响因子：
7.8
通讯作者：
Schwartz, Martin Alexander
中科院分区：
文献类型：
--
作者：
Orr, A Wayne;Stockton, Rebecca;Simmers, Michael B;Sanders, John M;Sarembock, Ian J;Blackman, Brett R;Schwartz, Martin Alexander
内皮通透性的升高被认为是动脉粥样硬化形成的关键，因为它允许循环脂蛋白进入内皮下单核细胞。局部血流动力学和细胞因子可能共同控制动脉粥样硬化斑块的内皮通透性。我们最近发现p21激活激酶（PAK）调节内皮通透性。我们现在报告，液体流动，动脉粥样硬化的流量配置文件，氧化低密度脂蛋白，和促动脉粥样硬化细胞因子的发病都刺激PAK磷酸化和招聘到细胞-细胞连接。在所有情况下，与基底膜蛋白相比，在铺于纤连蛋白（FN）上的细胞中PAK的活化更高。在体内，PAK在动脉的动脉粥样硬化倾向区域被激活，并与内皮下的FN相关。在体内抑制PAK可降低动脉粥样硬化易感区域的通透性。因此，基质特异性PAK激活介导动脉粥样硬化形成中血管通透性升高。
Elevated permeability of the endothelium is thought to be crucial in atherogenesis because it allows circulating lipoproteins to access subendothelial monocytes. Both local hemodynamics and cytokines may govern endothelial permeability in atherosclerotic plaque. We recently found that p21-activated kinase (PAK) regulates endothelial permeability. We now report that onset of fluid flow, atherogenic flow profiles, oxidized LDL, and proatherosclerotic cytokines all stimulate PAK phosphorylation and recruitment to cell–cell junctions. Activation of PAK is higher in cells plated on fibronectin (FN) compared to basement membrane proteins in all cases. In vivo, PAK is activated in atherosclerosis-prone regions of arteries and correlates with FN in the subendothelium. Inhibiting PAK in vivo reduces permeability in atherosclerosis-prone regions. Matrix-specific PAK activation therefore mediates elevated vascular permeability in atherogenesis.