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1 Lung Biology Program, Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, Sophia Children Hospital, Rotterdam, The Netherlands
2 Lung Biology Program, Hospital for Sick Children, Toronto, ON, Canada
3 Department of Pediatrics, Sophia Children Hospital, Rotterdam, The Netherlands
* To whom correspondence should be addressed. E-mail: martin.post{at}sickkids.ca.
Recent investigations have suggested an active role for endothelial cells in organ development, including the lung. Herein, we investigated some of the molecular mechanisms underlying normal pulmonary vascular development and their influence on epithelial branching morphogenesis. Because the lung in utero develops in a relative hypoxic environment, we first investigated the influence of low oxygen on epithelial and vascular branching morphogenesis. Two transgenic mouse models, namely the C101-LacZ (epithelial-LacZ marker) and the Tie2-LacZ (endothelial-LacZ marker) mouse were used. At E11.5, primitive lung buds were dissected and cultured at either 20% or 3% oxygen. At 24-hour intervals, epithelial and endothelial LacZ gene expression was visualized by X-gal staining. The rate of branching of both tissue elements was increased in explants cultured at 3% oxygen compared to 20% oxygen. Low oxygen increased the expression of vascular endothelial growth factor (Vegf), but not that of the Vegf receptor (Flk-1). Expression of two crucial epithelial branching factors, fibroblast growth factor-10 (Fgf10) and bone morphogenetic protein-4 (Bmp4) were not affected by low oxygen. Epithelial differentiation was maintained at low oxygen as shown by SP-C in situ hybridization. To explore epithelial-vascular interactions, we inhibited vascular development with antisense oligonucleotides (ODNs) targeted against either hypoxia inducible factor (Hif)-1
or vascular endothelial growth factor (Vegf). Epithelial branching morphogenesis in vitro was dramatically abrogated when pulmonary vascular development was inhibited. Collectively, the in vitro data show that a low oxygen environment enhances branching of both distal lung epithelium and vascular tissue and that pulmonary vascular
development appears to be rate limiting for epithelial branching morphogenesis.
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