Epithelial-vascular cross talk mediated by VEGF-A and HGF signaling directs primary septae formation during distal lung morphogenesis.
There is increasing evidence that epithelial-vascular interactions are essential for tissue patterning. Here we identified components of the molecular cross talk between respiratory epithelial cells and pulmonary capillaries necessary for the formation of the gas exchange surface of the lung. Selective inactivation of the Vegf-A gene in respiratory epithelium results in an almost complete absence of pulmonary capillaries, demonstrating the dependence of pulmonary capillary development on epithelium-derived Vegf-A. Deficient capillary formation in Vegf-A deficient lungs is associated with a defect in primary septae formation, a morphogenetic process critical for distal lung morphogenesis, coupled with suppression of epithelial cell proliferation and decreased hepatocyte growth factor (Hgf) expression. Lung endothelial cells express Hgf, and selective deletion of the Hgf receptor gene in respiratory epithelium phenocopies the malformation of septae, confirming the requirement for epithelial Hgf signaling in normal septae formation and suggesting that Hgf serves as an endothelium-derived factor that signals to the epithelium. Our findings support a mechanism for primary septae formation dependent on reciprocal interactions between respiratory epithelium and the underlying vasculature, establishing the dependence of pulmonary capillary development on epithelium-derived Vegf-A, and identify Hgf as a putative endothelium-derived factor that mediates the reciprocal signaling from the vasculature to the respiratory epithelium.
Yamamoto
Hiroaki
H
Department of Medicine and Lung Biology Center, University of California, San Francisco, CA 94143, USA.
Yun
Eun Jun
EJ
Gerber
Hans-Peter
HP
Ferrara
Napoleone
N
Whitsett
Jeffrey A
JA
Vu
Thiennu H
TH
D000818:Animals; D001483:Base Sequence; D002196:Capillaries / Q000196:embryology / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D017931:DNA Primers / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D004848:Epithelium / Q000196:embryology / Q000378:metabolism; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D017403:In Situ Hybridization; D008168:Lung / Q000098:blood supply / Q000196:embryology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D011247:Pregnancy; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D005346:Fibroblast Growth Factors; D017228:Hepatocyte Growth Factor