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1: Development. 2007 Oct;134(20):3743-52. Epub 2007 Sep 19.

FGF9 and SHH regulate mesenchymal Vegfa expression and development of the
pulmonary capillary network.

White AC, Lavine KJ, Ornitz DM.

Department of Molecular Biology and Pharmacology, Washington University School of
Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, USA.

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.

PMID: 17881491 [PubMed - in process]

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