Age-dependent endothelial nitric oxide synthase uncoupling in pulmonary arteries of endoglin heterozygous mice
Age-dependent endothelial nitric oxide synthase uncoupling in pulmonary arteries of endoglin heterozygous mice
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DOI：
10.1152/ajplung.00168.2009
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发表时间：
2009-12-01
影响因子：
4.9
通讯作者：
Letarte, M.
中科院分区：
文献类型：
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作者：
Belik, J.;Jerkic, M.;Letarte, M.
Belik J，Jerkic M，McIntyre BA，Pan J，Leen J，Yu LX，Henkelman RM，Toporsian M，Letarte M。内皮糖蛋白杂合小鼠肺动脉中年龄依赖性内皮一氧化氮合酶解偶联。 Am J Physiol Lung Cell Mol Physiol 297：L1170-L1178，2009。首次发表于 2009 年 10 月 9 日； doi:10.1152/ajplung.00168.2009.-Endoglin 是一种对内皮细胞功能至关重要的 TGF-β 超家族受体。该基因的突变与 I 型遗传性出血性毛细血管扩张症 (HHT1) 相关，并且疾病的临床症状通常在晚年更加明显。我们之前表明，成年 Eng 杂合子 (Eng(+/-)) 小鼠的全身血管由于内皮一氧化氮合酶 (eNOS) 解偶联而表现出血管舒张作用增强。我们假设这些变化可能随着年龄的增长而发生，并与年龄匹配的同窝对照小鼠相比，评估了新生和成年 Eng(+/-) 小鼠的肺动脉 eNOS 依赖性、乙酰胆碱（ACh 诱导）血管舒张作用。虽然 ACh 诱导的血管舒张作用在所有新生小鼠中相似，但与对照血管相比，成年 Eng(+/-) 血管舒张作用显着增加。 L-NAME 抑制血管舒张反应，表明 eNOS 依赖性。在成年杂合小鼠（而非新生杂合小鼠）的肺组织中观察到 eNOS 解偶联，并且与成年 Eng(+/-) 与对照肺相比，eNOS 解偶联与活性 O-2 物种 (ROS) 的产生增加有关。有趣的是，成年小鼠的 ROS 生成量高于新生小鼠，NADPH 氧化酶 4 和 SOD 1、2、3 亚型的水平也更高。然而，成年 Eng(+/-) 肺中酶蛋白水平和 NADPH 活性正常，表明 ROS 生成和清除的发育成熟不能解释成年 Eng(+/-) 小鼠中观察到的血管舒张增加。我们的数据表明，Eng(+/-) 肺中 eNOS 依赖性 H2O2 的产生是肺血管舒张作用增强的原因。在这些小鼠模仿人类 HHT1 的程度上，与年龄相关的肺血管 eNOS 解偶联可能解释了儿童晚期和成人临床肺部表现的发病。
Belik J, Jerkic M, McIntyre BA, Pan J, Leen J, Yu LX, Henkelman RM, Toporsian M, Letarte M. Age-dependent endothelial nitric oxide synthase uncoupling in pulmonary arteries of endoglin heterozygous mice. Am J Physiol Lung Cell Mol Physiol 297: L1170-L1178, 2009. First published October 9, 2009; doi:10.1152/ajplung.00168.2009.-Endoglin is a TGF-beta superfamily receptor critical for endothelial cell function. Mutations in this gene are associated with hereditary hemorrhagic telangiectasia type I (HHT1), and clinical signs of disease are generally more evident later in life. We previously showed that systemic vessels of adult Eng heterozygous (Eng(+/-)) mice exhibit increased vasorelaxation due to uncoupling of endothelial nitric oxide synthase (eNOS). We postulated that these changes may develop with age and evaluated pulmonary arteries from newborn and adult Eng(+/-) mice for eNOS-dependent, acetylcholine (ACh-induced) vasorelaxation, compared with that of age-matched littermate controls. While ACh-induced vasorelaxation was similar in all newborn mice, it was significantly increased in the adult Eng(+/-) vs. control vessels. The vasodilatory responses were inhibited by L-NAME suggesting eNOS dependence. eNOS uncoupling was observed in lung tissues of adult, but not newborn, heterozygous mice and was associated with increased production of reactive O-2 species (ROS) in adult Eng(+/-) vs. control lungs. Interestingly, ROS generation was higher in adult than newborn mice and so were the levels of NADPH oxidase 4 and SOD 1, 2, 3 isoforms. However, enzyme protein levels and NADPH activity were normal in adult Eng(+/-) lungs indicating that the developmental maturation of ROS generation and scavenging cannot account for the increased vasodilatation observed in adult Eng(+/-) mice. Our data suggest that eNOS-dependent H2O2 generation in Eng(+/-) lungs accounts for the heightened pulmonary vasorelaxation. To the extent that these mice mimic human HHT1, age-associated pulmonary vascular eNOS uncoupling may explain the late childhood and adult onset of clinical lung manifestations.