Everett A D, Le Cras T D, Xue C, Johns R A
Department of Pediatrics, University of Virginia, Charlottesville, Virginia 22908, USA.
Am J Physiol. 1998 Jun;274(6):L1058-65. doi: 10.1152/ajplung.1998.274.6.L1058.
Congenital heart lesions resulting in increased pulmonary blood flow are common and if unrepaired often lead to pulmonary hypertension and heart failure. Therefore, we hypothesized that increased pulmonary blood flow without changes in pressure would result in remodeling of the pulmonary arterial wall. Furthermore, because the vasodilator nitric oxide is produced by the lung, is regulated by flow in the systemic circulation, and has been associated with the regulation of smooth muscle cell proliferation, we hypothesized that increased pulmonary blood flow would result in altered expression of endothelial nitric oxide synthase (eNOS). To study this hypothesis, 42-day-old Sprague-Dawley rats had creation of an aortocaval shunt to increase pulmonary blood flow for 6 wk. The shunt resulted in a significant increase in the heart- and lung-to-body weight ratios (>2-fold; P < 0.05) without significant alteration of pulmonary or systemic blood pressures. Significant thickening of the pulmonary arterial medial wall developed, with increased muscularization of small (50-100 micron)- and medium (101-200 micron)-sized arteries as evidenced by alpha-actin smooth muscle staining. Proliferating cell nuclear antigen staining and bromodeoxyuridine labeling did not detect proliferating smooth muscle cells in the vascular wall. eNOS Western and Northern blot analyses and immunohistochemical staining demonstrated that eNOS protein and mRNA levels were not altered in the shunt lungs compared with sham controls. Therefore, increased pulmonary flow without increased pressure resulted in pulmonary artery medial thickening, without ongoing proliferation. Unlike chronic hypoxia-induced vascular remodeling, the pulmonary vascular remodeling resulting from increased pulmonary blood flow is not associated with changes in eNOS.
导致肺血流量增加的先天性心脏病变很常见，如果不进行修复，常常会导致肺动脉高压和心力衰竭。因此，我们推测在压力不变的情况下肺血流量增加会导致肺动脉壁重塑。此外，由于血管舒张剂一氧化氮由肺产生，受体循环中的血流调节，并且与平滑肌细胞增殖的调节有关，我们推测肺血流量增加会导致内皮型一氧化氮合酶（eNOS）表达改变。为了研究这一假设，对42日龄的Sprague-Dawley大鼠建立主动脉腔静脉分流术以增加肺血流量，持续6周。分流导致心脏和肺与体重的比值显著增加（>2倍；P<0.05），而肺动脉或体循环血压无显著改变。肺动脉中膜壁明显增厚，小（50-100微米）和中（101-200微米）动脉的肌化增加，α-肌动蛋白平滑肌染色可证明这一点。增殖细胞核抗原染色和溴脱氧尿苷标记未检测到血管壁中有增殖的平滑肌细胞。eNOS的蛋白质免疫印迹和Northern印迹分析以及免疫组织化学染色表明，与假手术对照组相比，分流肺中的eNOS蛋白和mRNA水平未发生改变。因此，压力未升高但肺血流量增加导致肺动脉中膜增厚，且无持续增殖。与慢性缺氧诱导的血管重塑不同，肺血流量增加导致的肺血管重塑与eNOS的变化无关。
