Pulmonary hypertension in TNF-α-overexpressing mice is associated with decreased VEGF gene expression
Pulmonary hypertension in TNF-α-overexpressing mice is associated with decreased VEGF gene expression
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DOI：
10.1152/japplphysiol.00083.2002
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发表时间：
2002-12-01
影响因子：
3.3
通讯作者：
Fagan, KA
中科院分区：
文献类型：
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作者：
Fujita, M;Mason, RJ;Fagan, KA
肿瘤坏死因子- α (tnf - α)转基因小鼠先前被发现具有与肺气肿和严重肺动脉高压一致的特征。慢性炎症和血管周围纤维化导致肺泡增大和间质增厚。在本报告中，我们试图确定导致tnf - α转基因小鼠肺动脉高压发展的潜在机制。为了确定持续血管收缩是否是肺动脉高压的重要组成部分，给予一氧化氮并测量血流动力学。一氧化氮（25 ppm）不能使转基因阳性小鼠的右心室压力正常化，这表明肺动脉高压不是由于持续的血管收缩。肺动脉结构分析发现，转基因阳性小鼠的肺动脉外膜增厚，并有内侧肥大的趋势，表明血管重构已经发生。超声心动图测量左心室缩短百分比作为体内心室功能的测量显示，左心室功能障碍不会导致肺动脉高压。我们检测了已知在血管张力和结构调节中重要的基因的表达。血管内皮生长因子及其受体flk-1的信使RNA表达与转基因阴性幼崽相比均有所降低。内皮和诱导型一氧化氮合酶mRNA水平在两组中相似。tnf - α转基因小鼠的内皮素-1 mRNA表达也降低。有趣的是，雌性转基因小鼠的存活率比雄性转基因小鼠低。我们得出结论，tnf - α的慢性过表达与血管内皮生长因子和flk-1基因表达降低、肺血管重塑和严重肺动脉高压有关，尽管其确切机制尚不清楚。
Tumor necrosis factor-alpha (TNF-alpha) transgenic mice have previously been found to have characteristics consistent with emphysema and severe pulmonary hypertension. Lungs demonstrated alveolar enlargement as well as interstitial thickening due to chronic inflammation and perivascular fibrosis. In the present report, we sought to determine potential mechanisms leading to development of pulmonary hypertension in TNF-alpha transgenic mice. To determine whether sustained vasoconstriction was an important component of this pulmonary hypertension, nitric oxide was administered and hemodynamics were measured. Nitric oxide (25 ppm) failed to normalize right ventricular pressure in transgene-positive mice, suggesting that the pulmonary hypertension was not due to sustained vasoconstriction. Structural analysis of the pulmonary arteries found adventitial thickening and a trend toward medial hypertrophy in pulmonary arteries of transgene-positive mice, suggesting that vascular remodeling had occurred. Echocardiographic measurement of the percent fractional shortening of the left ventricle as a measurement of ventricular function in vivo revealed that left ventricular dysfunction was not contributing to pulmonary hypertension. We examined expression of genes known to be important in regulation of vascular tone and structure. Messenger RNA expression of vascular endothelial growth factor and its receptor flk-1 was reduced compared with transgene-negative littermates at all ages. Endothelial and inducible nitric oxide synthase mRNA levels were similar in both groups. Endothelin-1 mRNA was also decreased in TNF-alpha transgenic mice. Interestingly, female transgenic mice had decreased survival rate compared with male transgenic mice. We conclude that chronic overexpression of TNF-alpha is associated with decreased vascular endothelial growth factor and flk-1 gene expression, pulmonary vascular remodeling, and severe pulmonary hypertension, although the precise mechanism is unknown.