Defect in microvascular adaptation to chronic changes in blood flow in mice lacking the gene encoding for dystrophin
Defect in microvascular adaptation to chronic changes in blood flow in mice lacking the gene encoding for dystrophin
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DOI：
10.1161/01.res.0000047505.11002.81
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发表时间：
2002-12-13
影响因子：
20.1
通讯作者：
Henrion, D
中科院分区：
文献类型：
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作者：
Loufrani, L;Levy, BI;Henrion, D
肌营养不良蛋白在横纹肌的机械转导中起关键作用。在缺乏dystrophin编码基因的小鼠(MDX小鼠)中，dystrophin和其他几种dystrophin-糖蛋白复合体蛋白的缺失导致了血流(剪应力)介导的NO依赖的扩张(FMD)的缺陷。由于内皮对于动脉适应血流的慢性变化是必不可少的，这种血管缺陷的长期后果可能会影响血流诱导的血管重塑。因此，我们通过交替结扎动脉，使小鼠肠系膜阻力动脉发生慢性血流变化。因此，动脉处于高流量(HF)、低流量(LF)或正常流量状态。2周后，在动脉造影术中对动脉进行体外研究。在MDX小鼠的HF动脉中发现直径增加(从174+/-10微米增加到210+/-15微米，压力75毫米汞柱)并不显著。对照组和mdx组小鼠的LF动脉管径减小相似。HF动脉FMD升高，LF动脉FMD降低。Mdx组小鼠HF动脉FMD无明显增加。NO依赖的FMD和NO合成酶在对照组小鼠HF动脉中的表达增加，而在MDX小鼠中不表达。两个品系的HF动脉的舒张性和收缩张力不受影响，而LF动脉的舒张性和收缩张力则降低。我们的结论是，MDX小鼠的阻力动脉不能很好地适应慢性血流变化，因为在接受HF 2周的MDX小鼠中，管径增加，内皮一氧化氮合酶表达增加，FMD没有发生。这项研究表明，在肌营养不良蛋白相关的肌病中，血流调节可能受到干扰，可能会增加器官损伤。
Dystrophin has a key role in striated muscle mechanotransduction. In mice lacking the gene encoding for dystrophin (mdx mice), the absence of dystrophin and several other proteins of the dystrophin-glycoprotein complex induces a defect in flow (shear stress)-mediated NO-dependent dilation (FMD). Because the endothelium is essential for the adaptation of arteries to chronic changes in blood flow, the long-term consequences of this vascular deficiency might affect flow-induced vascular remodeling. Thus, we submitted mouse mesenteric resistance arteries to chronic changes in flow by alternatively ligating arteries. Arteries were thus submitted to high flow (HF), low flow (LF), or normal flow. After 2 weeks, arteries were studied in vitro in an arteriograph. Increases in diameter (from 174 +/- 10 to 210 +/- 15 mum, pressure 75 mm Hg) found in HF arteries were not significant in mdx mice. Arterial diameters in LF arteries decreased similarly in control and mdx mice. FMD increased in HF arteries and decreased in LF arteries. FMD was not increased in HF arteries in mdx mice. NO-dependent FMD and NO synthase expression increased in the HF arteries of control mice but not in those of mdx mice. Dilatory and contractile tone, depending on the smooth muscle, was unaffected in HF arteries but decreased in LF arteries of both strains. We conclude that resistance arteries of mdx mice do not adapt properly to chronic changes in flow, inasmuch as the increases in diameter, endothelial NO synthase expression, and FMD did not occur in mdx mice submitted to HF for 2 weeks. This study suggests that blood flow regulation might be disturbed in dystrophin-related myopathies, possibly increasing organ damage.