FGF9 and SHH regulate mesenchymal Vegfa expression and development of the pulmonary capillary network
FGF9 and SHH regulate mesenchymal Vegfa expression and development of the pulmonary capillary network
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DOI：
10.1242/dev.004879
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发表时间：
2007-10-15
期刊：
影响因子：
4.6
通讯作者：
Ornitz, David M.
中科院分区：
文献类型：
--
作者：
White, Andrew C.;Lavine, Kory J.;Ornitz, David M.
密集的毛细血管网与肺上皮细胞的并列对于空气-血液气体交换是必不可少的。肺血管发育不良可导致支气管肺发育不良和肺泡毛细血管发育不良。虽然血管内皮生长因子A（Vegfa）是肺毛细血管网形成所必需的，但关于调节远端毛细血管丛的密度和位置以及Vegfa的表达模式的因子知之甚少。在这里，我们表明，成纤维细胞生长因子9（FGF 9）和音刺猬（SHH）信号肺间充质，但不是内皮细胞，是每个必要的，并在一起足够的远端毛细血管的发展。此外，FGF 9功能的获得和丧失都调节肺间质中的Vegfa表达，并且VEGF信号传导是FGF 9介导的血管形成所需的.然而，FGF 9只能部分挽救在没有SHH信号传导的情况下发现的毛细血管密度的降低，并且SHH不能挽救在Fgf 9（-/-）肺中发现的血管表型。因此，这两种信号系统调节远端肺间充质中血管发育的不同方面。这些数据表明，通过FGF 9和SHH信号协调控制肺毛细血管丛的生长和图案化，并调节Vegfa的时空表达的分子机制。
The juxtaposition of a dense capillary network to lung epithelial cells is essential for air- blood gas exchange. Defective lung vascular development can result in bronchopulmonary dysplasia and alveolar capillary dysplasia. Although vascular endothelial growth factor A ( Vegfa) is required for formation of the lung capillary network, little is known regarding the factors that regulate the density and location of the distal capillary plexus and the expression pattern of Vegfa. Here, we show that fibroblast growth factor 9 ( FGF9) and sonic hedgehog ( SHH) signaling to lung mesenchyme, but not to endothelial cells, are each necessary and together sufficient for distal capillary development. Furthermore, both gain- and loss- of- function of FGF9 regulates Vegfa expression in lung mesenchyme, and VEGF signaling is required for FGF9- mediated blood vessel formation. FGF9, however, can only partially rescue the reduction in capillary density found in the absence of SHH signaling, and SHH is unable to rescue the vascular phenotype found in Fgf9(-/-) lungs. Thus, both signaling systems regulate distinct aspects of vascular development in distal lung mesenchyme. These data suggest a molecular mechanism through which FGF9 and SHH signaling coordinately control the growth and patterning of the lung capillary plexus, and regulate the temporal and spatial expression of Vegfa.