Le Cras T D, Tyler R C, Horan M P, Morris K G, Tuder R M, McMurtry I F, Johns R A, Abman S H
Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
J Clin Invest. 1998 Feb 15;101(4):795-801. doi: 10.1172/JCI786.
Mechanisms that regulate endothelial nitric oxide synthase (eNOS) expression in normal and hypoxic pulmonary circulation are poorly understood. Lung eNOS expression is increased after chronic hypoxic pulmonary hypertension in rats, but whether this increase is due to altered hemodynamics or to hypoxia is unknown. Therefore, to determine the effect of blood flow changes on eNOS expression in the normal pulmonary circulation, and to determine whether the increase in eNOS expression after chronic hypoxia is caused by hemodynamic changes or low oxygen tension, we compared eNOS expression in the left and right lungs of normoxic and chronically hypoxic rats with surgical stenosis of the left pulmonary artery (LPA). LPA stenosis in normoxic rats reduced blood flow to the left lung from 9.8+/-0.9 to 0.8+/-0.4 ml/100 mg/min (sham surgery controls vs. LPA stenosis, P < 0.05), but there was not a significant increase in right lung blood flow. When compared with the right lung, eNOS protein and mRNA content in the left lung was decreased by 32+/-7 and 54+/-13%, respectively (P < 0.05), and right lung eNOS protein content was unchanged. After 3 wk of hypoxia, LPA stenosis reduced blood flow to the left lung from 5.8+/-0.6 to 1.5+/-0.4 ml/100 mg/min, and increased blood flow to the right lung from 5.8+/-0.5 to 10.0+/-1.4 ml/ 100 mg/min (sham surgery controls vs. LPA stenosis, P < 0.05). Despite reduced flow and pressure to the left lung and increased flow and pressure to the right lung, left and right lung eNOS protein and mRNA contents were not different. There were also no differences in lung eNOS protein levels when compared with chronically hypoxic sham surgery controls (P > 0.05). We conclude that reduction of pulmonary blood flow decreases eNOS mRNA and protein expression in normoxic adult rat lungs, and that hypoxia increases eNOS expression independently of changes in hemodynamics. These findings demonstrate that hemodynamic forces maintain eNOS content in the normoxic pulmonary circulation of the adult rat, and suggest that chronic hypoxia increases eNOS expression independently of changes in hemodynamics.
在正常和低氧性肺循环中调节内皮型一氧化氮合酶（eNOS）表达的机制尚不清楚。大鼠慢性低氧性肺动脉高压后肺eNOS表达增加，但这种增加是由于血流动力学改变还是低氧所致尚不清楚。因此，为了确定血流变化对正常肺循环中eNOS表达的影响，并确定慢性低氧后eNOS表达增加是由血流动力学变化还是低氧张力引起的，我们比较了正常氧合和慢性低氧大鼠左肺动脉（LPA）手术狭窄后左、右肺的eNOS表达。正常氧合大鼠的LPA狭窄使左肺血流从9.8±0.9降至0.8±0.4 ml/100 mg/min（假手术对照组与LPA狭窄组，P<0.05），但右肺血流无显著增加。与右肺相比，左肺eNOS蛋白和mRNA含量分别降低了32±7%和54±13%（P<0.05），右肺eNOS蛋白含量未改变。低氧3周后，LPA狭窄使左肺血流从5.8±0.6降至1.5±0.4 ml/100 mg/min，并使右肺血流从5.8±0.5增至10.0±1.4 ml/100 mg/min（假手术对照组与LPA狭窄组，P<0.05）。尽管左肺血流和压力降低，右肺血流和压力增加，但左、右肺eNOS蛋白和mRNA含量无差异。与慢性低氧假手术对照组相比，肺eNOS蛋白水平也无差异（P>0.05）。我们得出结论，肺血流减少会降低正常氧合成年大鼠肺中eNOS mRNA和蛋白表达，低氧会独立于血流动力学变化增加eNOS表达。这些发现表明血流动力学力维持成年大鼠正常氧合肺循环中的eNOS含量，并提示慢性低氧独立于血流动力学变化增加eNOS表达。
