Loss of HIF-2 and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice
Loss of HIF-2 and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice
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DOI：
10.1038/nm721
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发表时间：
2002-07-01
期刊：
影响因子：
82.9
通讯作者：
Carmeliet, P
中科院分区：
文献类型：
--
作者：
Compernolle, V;Brusselmans, K;Carmeliet, P
呼吸窘迫综合征（RDS）是一种常见且严重的早产并发症。在这里，我们报道了缺氧诱导转录因子- 2α (hif - 2α)的缺失导致新生小鼠致命的RDS，原因是肺泡2型细胞产生的表面活性剂不足。VEGF是HIF-2alpha的靶标，它调节胎儿肺成熟：因为在HIF-2alpha缺乏的胎儿中，肺泡细胞中的VEGF水平降低；缺乏VEGF（164）和VEGF（188）亚型或VEGF启动子中hif结合位点的小鼠死于RDS；宫内输送抗VEGF-受体-2抗体引起RDS， VEGF刺激培养的2型肺细胞产生表面活性剂蛋白。宫内分娩或产后气管内灌注VEGF刺激糖原向表面活性剂的转化，保护早产小鼠抗RDS。VEGF的肺营养作用可能对早产儿肺成熟具有治疗潜力。
Respiratory distress syndrome (RDS) due to insufficient production of surfactant is a common and severe complication of preterm delivery. Here, we report that loss of the hypoxia-inducible transcription factor-2alpha (HIF-2alpha) caused fatal RDS in neonatal mice due to insufficient surfactant production by alveolar type 2 cells. VEGF, a target of HIF-2alpha, regulates fetal lung maturation: because VEGF levels in alveolar cells were reduced in HIF-2alpha-deficient fetuses; mice with a deficiency of the VEGF(164) and VEGF(188) isoforms or of the HIF-binding site in the VEGF promotor died of RDS; intrauterine delivery of anti-VEGF-receptor-2 antibodies caused RDS and VEGF stimulated production of surfactant proteins by cultured type 2 pneumocytes. Intrauterine delivery or postnatal intratracheal instillation of VEGF stimulated conversion of glycogen to surfactant and protected preterm mice against RDS. The pneumotrophic effect of VEGF may have therapeutic potential for lung maturation in preterm infants.