Chronic hypoxia induces Rho kinase-dependent myogenic tone in small pulmonary arteries
Chronic hypoxia induces Rho kinase-dependent myogenic tone in small pulmonary arteries
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DOI：
10.1152/ajplung.00253.2007
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发表时间：
2008-04-01
影响因子：
4.9
通讯作者：
Resta, Thomas C.
中科院分区：
文献类型：
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作者：
Broughton, Brad R. S.;Walker, Benjimen R.;Resta, Thomas C.
含氧量正常的成年动物的肺血管中的肌张力极小或不存在。尽管慢性缺氧（CH）会增加肺动脉的基础张力，但尚不清楚这种张力升高的一部分是否是由于肌原性的发展。由于CH增强了基底动脉RhoA活性和Rho激酶（ROK）表达，我们假设CH通过ROK依赖的血管平滑肌（VSM）Ca（2+）敏化来增强肺动脉中的肌源性反应。为了验证这一假设，我们评估了ROK对对照组和CH组大鼠（0.5大气压下4周）内皮破裂肺动脉[内径（ID）为50-300 μ m]的基础张力和压力诱导的血管收缩的作用。用Fura-2 AM负载动脉，连续监测VSM细胞内Ca（2+）浓度（[Ca（2+）]（i））。基础VSM [Ca（2+）]（i）在组间无差异。ROK抑制剂HA-1077（100 nM至30 μ M）引起CH动脉中基础张力的浓度依赖性降低，但在对照血管中无影响。相比之下，PKC抑制GF 109203 X（1 μ M）没有改变基础张力。此外，在CH大鼠的动脉（50 - 200 μ m ID）中，在12、15、25和35 mmHg下观察到对管腔内压力（5 - 45 mmHg）逐步增加的显著血管收缩反应。HA-1077（10 μ M）可消除这种肌原性反应，但GF 109203 X不能消除这种反应。VSM [Ca（2+）]（i）未被HA-1077、GF 109203 X或任一组中的压力增加改变。在较大血管（200 - 300 μ m ID）中未观察到肌原性。我们的结论是CH通过ROK依赖性肌丝Ca（2+）敏化诱导小肺动脉肌源性张力。
Myogenic tone in the pulmonary vasculature of normoxic adult animals is minimal or nonexistent. Whereas chronic hypoxia (CH) increases basal tone in pulmonary arteries, it is unclear if a portion of this elevated tone is due to development of myogenicity. Since basal arterial RhoA activity and Rho kinase (ROK) expression are augmented by CH, we hypothesized that CH elicits myogenic reactivity in pulmonary arteries through ROK-dependent vascular smooth muscle (VSM) Ca(2+) sensitization. To test this hypothesis, we assessed the contribution of ROK to basal tone and pressure-induced vasoconstriction in endothelium-disrupted pulmonary arteries [50-300 mu m inner diameter (ID)] from control and CH [4 wk at 0.5 atmosphere (atm)] rats. Arteries were loaded with fura-2 AM to continuously monitor VSM intracellular Ca(2+) concentration ([Ca(2+)](i)). Basal VSM [Ca(2+)](i) was not different between groups. The ROK inhibitor, HA-1077 (100 nM to 30 mu M), caused a concentration-dependent reduction of basal tone in CH arteries but had no effect in control vessels. In contrast, PKC inhibition with GF109203X (1 mu M) did not alter basal tone. Furthermore, significant vasoconstriction in response to stepwise increases in intraluminal pressure (5 - 45 mmHg) was observed at 12, 15, 25, and 35 mmHg in arteries (50 - 200 mu m ID) from CH rats. This myogenic reactivity was abolished by HA-1077 (10 mu M) but not by GF109203X. VSM [Ca(2+)](i) was unaltered by HA-1077, GF109203X, or increases in pressure in either group. Myogenicity was not observed in larger vessels (200 - 300 mu m ID). We conclude that CH induces myogenic tone in small pulmonary arteries through ROK-dependent myofilament Ca(2+) sensitization.