The pulmonary circulation of homozygous of heterozygous eNOS-null mice is hyperresponsive to mild hypoxia
The pulmonary circulation of homozygous of heterozygous eNOS-null mice is hyperresponsive to mild hypoxia
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DOI：
10.1172/jci3862
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发表时间：
1999-01-01
影响因子：
15.9
通讯作者：
Rodman, DM
中科院分区：
文献类型：
--
作者：
Fagan, KA;Fouty, BW;Rodman, DM
急性缺氧性血管收缩和缺氧性肺动脉高压(PHTN)是肺循环的独特特性。肺内皮细胞产生血管活性因子，包括一氧化氮(NO)，以改变这些现象。我们利用内皮型一氧化氮合酶(ENOS)基因的靶向阻断(eNOS(-/-))小鼠，验证了内皮型一氧化氮合酶(ENOS)产生的NO调节肺血管对低氧反应的假说。在轻度缺氧条件下饲养的eNOS(-/-)小鼠与对照组或在模拟海平面条件下饲养的eNOS(-/-)小鼠相比，发现明显的PHTN。我们发现，与对照组相比，eNOS(-/-)小鼠部分和完全肌化的远端肺动脉增加了近两倍。与血管收缩是PHTN的主要机制一致，然而，急性吸入25ppm NO可使eNOS(-/-)小鼠的RV压力恢复正常。除了对eNOS(-/-)小鼠的研究外，还使用杂合子eNOS(+/-)小鼠来测试eNOS的剂量效应。尽管eNOS(+/-)小鼠的肺组织中有50%的正常eNOS蛋白，但对低氧的反应与eNOS(-/-)小鼠没有区别。我们认为内皮型一氧化氮合酶是肺血管对慢性低氧反应的重要调节因子，超过50%的内皮型一氧化氮合酶表达是维持正常肺血管张力所必需的。
Acute hypoxic vasoconstriction and development of hypoxic pulmonary hypertension (PHTN) are unique properties of the pulmonary circulation. The pulmonary endothelium produces vasoactive factors, including nitric oxide (NO), that modify these phenomena. We tested the hypothesis that NO produced by endothelial nitric oxide synthase (eNOS) modulates pulmonary vascular responses to hypoxia using mice with targeted disruption of the eNOS gene (eNOS(-/-)). Marked PHTN was found in eNOS(-/-) mice raised in mild hypoxia when compared with either controls or eNOS(-/-) mice raised in conditions simulating sea level. We found an approximate twofold increase in partially and fully muscularized distal pulmonary arteries in eNOS(-/-) mice compared with controls. Consistent with vasoconstriction being the primary mechanism of PHTN, however, acute inhalation of 25 ppm NO resulted in normalization of RV pressure in eNOS(-/-) mice. In addition to studies of eNOS(-/-) mice, the dose-effect of eNOS was tested using heterozygous eNOS(+/-) mice. Although the lungs of eNOS(+/-) mice had 50% of normal eNOS protein, the response to hypoxia was indistinguishable from that of eNOS(-/-) mice. We conclude that eNOS-derived NO is an important modulator of the pulmonary vascular response to chronic hypoxia and that more than 50% of eNOS expression is required to maintain normal pulmonary vascular tone.