Inhaled nitric oxide attenuates pulmonary hypertension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor
Inhaled nitric oxide attenuates pulmonary hypertension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor
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DOI：
10.1152/ajplung.00291.2003
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发表时间：
2004-08-01
影响因子：
4.9
通讯作者：
Abman, SH
中科院分区：
文献类型：
--
作者：
Tang, JR;Markham, NE;Abman, SH
VEGF在肺发育过程中起关键作用，在患有支气管肺发育不良的人类婴儿中减少。新生大鼠中VEGF受体的抑制降低血管生长和肺泡形成并导致肺动脉高压（PH）。一氧化氮（NO）是VEGF的下游介质，但VEGF信号传导受损的影响是否是由于NO产生减少而引起的尚不清楚。因此，我们试图确定是否受损的VEGF信号转导下调内皮NO合酶（eNOS）的表达在发育中的肺，是否吸入NO（iNO）降低PH和改善VEGF抑制后的肺生长。新生大鼠皮下注射SU-5416（一种VEGF受体抑制剂）或溶剂单次给药，并在3周龄时处死，以评估离体灌注肺（IPL）中的右心室肥大（RVH）、径向肺泡计数（RAC）、肺eNOS蛋白和NOx生成。SU-5416的新生处理增加了幼鼠的RVH，降低了RAC。与对照组相比，SU-5416在第5天使肺eNOS蛋白表达降低89%（P < 0.01）。第14天大鼠的IPL研究显示，SU-5416给药后，基线肺动脉压升高，灌注液NOx浓度降低。重要的是，在SU-5416治疗后，iNO治疗可防止RVH增加并改善RAC。我们的结论是，SU-5416治疗新生大鼠下调肺eNOS表达，NO治疗降低PH，改善SU-5416治疗后的肺生长。我们推测，减少NO的产生有助于PH和减少VEGF信号受损引起的远端肺生长。
VEGF plays a critical role during lung development and is decreased in human infants with bronchopulmonary dysplasia. Inhibition of VEGF receptors in the newborn rat decreases vascular growth and alveolarization and causes pulmonary hypertension (PH). Nitric oxide ( NO) is a downstream mediator of VEGF, but whether the effects of impaired VEGF signaling are due to decreased NO production is unknown. Therefore, we sought to determine whether impaired VEGF signaling downregulates endothelial NO synthase ( eNOS) expression in the developing lung and whether inhaled NO (iNO) decreases PH and improves lung growth after VEGF inhibition. Newborn rats received a single dose of SU-5416 ( a VEGF receptor inhibitor) or vehicle by subcutaneous injection and were killed up to 3 wk of age for assessments of right ventricular hypertrophy (RVH), radial alveolar counts (RAC), lung eNOS protein, and NOx production in isolated perfused lungs (IPL). Neonatal treatment with SU-5416 increased RVH in infant rats and reduced RAC. Compared with controls, SU-5416 reduced lung eNOS protein expression by 89% at 5 days ( P < 0.01). IPL studies from day 14 rats demonstrated increased baseline pulmonary artery pressure and lower perfusate NOx concentration after SU-5416 treatment. Importantly, iNO treatment prevented the increase in RVH and improved RAC after SU-5416 treatment. We conclude that treatment of neonatal rats with SU-5416 downregulates lung eNOS expression and that iNO therapy decreases PH and improves lung growth after SU-5416 treatment. We speculate that decreased NO production contributes to PH and decreases distal lung growth caused by impaired VEGF signaling.