Inhaled nitric oxide attenuates pulmonary hypertension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor

Jen Ruey Tang, Neil E. Markham, Yuh Jyh Lin, Ivan F. McMurtry, Anne Maxey, John P. Kinsella, Steven H. Abman

研究成果: Article同行評審

184 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)L344-L351
期刊American Journal of Physiology - Lung Cellular and Molecular Physiology
287
發行號2 31-2
DOIs
出版狀態Published - 2004 8月

All Science Journal Classification (ASJC) codes

  • 生理學
  • 肺和呼吸系統醫學
  • 生理學(醫學)
  • 細胞生物學

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