Defective pulmonary development in the absence of heparin-binding vascular endothelial growth factor isoforms
Defective pulmonary development in the absence of heparin-binding vascular endothelial growth factor isoforms
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DOI：
10.1165/ajrcmb.27.2.4703
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发表时间：
2002-08-01
影响因子：
6.4
通讯作者：
deMello, DE
中科院分区：
文献类型：
--
作者：
Galambos, C;Ng, YS;deMello, DE
胎儿气道、肺泡和肺血管的发育是一个精确控制的过程。其中一种生长因子，血管内皮生长因子（VEGF），对胚胎发育至关重要，在小鼠中，消除一个等位基因是致命的。在肺发育的早期阶段，小鼠VEGF基因以不同的时空模式表达三种亚型（120、164和188），表明每种亚型具有特定的功能。我们设计了只表达VEGF 120的小鼠，以研究VEGF亚型在肺发育中的作用。通过肺血管Mercox铸型的扫描电子显微镜研究这些小鼠的肺血管发育。通过光学显微镜、透射电子显微镜、免疫组织化学和形态计量学分析气道和气-血屏障的发育。在所有VEGF 120/120胎仔和幼仔中，与120/+和野生型同窝仔相比，肺血管管型较小且密度较低。尽管所有三种基因型中腺泡前血管的世代计数相似，但与120/+和野生型同窝仔相比，所有年龄组的120/120胎仔中大多数外周血管扩张且分离更广泛。此外，与120/+和野生型同窝仔相比，120/120只动物的空气-血液屏障较少，空气空间-实质比降低。我们的结论是，VEGF 164和188亚型的缺乏损害肺微血管的发展和延迟空域成熟，表明肝素结合VEGF亚型在正常肺发育中的重要作用。
Development of the airways, alveoli, and the pulmonary vasculature in the fetus is a process that is precisely controlled. One of the growth factors involved, vascular endothelial growth factor (VEGF), is so critical for embryonic development that in the mouse, elimination of just a single allele is lethal. In the early stages of lung development, the mouse VEGF gene expresses three isoforms (120, 164, and 188) in a distinct temporo-spatial pattern, suggesting a specific function for each. We engineered mice that express only VEGF 120, to study the role of VEGF isoforms in lung development. Lung vessel development in these mice was studied by scanning electron microscopy of Mercox casts of lung vasculature. Airway and air-blood barrier development was analyzed by light microscopy, transmission electron microscopy, immunohistochemistry, and morphometry. In all VEGF120/120 fetuses and pups, lung vascular casts were smaller and less dense compared with 120/+ and wild-type littermates. Although the generation count of pre-acinar vessels was similar in all three genotypes, the most peripheral vessels were dilated and were more widely separated in 120/120 fetuses of all ages compared with 120/+ and wild-type littermates. In addition, 120/120 animals had fewer air-blood barriers and a decreased airspace-parenchyma ratio compared with 120/+ and wild-type littermates. We concluded that the absence of VEGF 164 and 188 isoforms impairs lung microvascular development and delays airspace maturatiort, indicating an essential role for heparin-binding VEGF isoforms in normal lung development.