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We hypothesized that this mechanism coordinates vasculogenesis with the fibroblast growth factor (FGF)-10\/FGF-receptor2b\/Spry2 regulator of airway branching. First, we tested if the HIF-1\u03b1 TOS motif participated in epithelial-mesenchymal vascular signaling. mTORC1 activation by insulin significantly amplified HIF-1\u03b1 activity at fetal Po<jats:sub>2<\/jats:sub>(23 mmHg) in human bronchial epithelium (16HBE14o-) and induced vascular traits (Flk1, sprouting) in cocultured human embryonic lung mesenchyme (HEL-12469). This enhanced activation of HIF-1\u03b1 by mTORC1 was abolished on expression of a HIF-1\u03b1 (F99A) TOS-mutant and also suppressed vascular differentiation of HEL-12469 cocultures. Next, we determined if vasculogenesis in fetal lung involved regulation of mTORC1 by the FGF-10\/FGFR2b\/Spry2 pathway. Fetal airway epithelium displayed distinct mTORC1 activity in situ, and its hyperactivation by TSC1<jats:sup>\u2212\/\u2212<\/jats:sup>knockout induced widespread VEGF expression and disaggregation of Tie2-positive vascular bundles. FGF-10-coated beads grafted into fetal lung explants from Tie2-LacZ transgenic mice induced localized vascular differentiation in the peripheral mesenchyme. In rat fetal distal lung epithelial (FDLE) cells cultured at fetal Po<jats:sub>2<\/jats:sub>, FGF-10 induced mTORC1 and amplified HIF-1\u03b1 activity and VEGF secretion without induction of ERK1\/2. This was accompanied by the formation of a complex between Spry2, the cCBL ubiquitin ligase, and the mTOR repressor, TSC2, which abolished GTPase activity directed against Rheb, the G protein inducer of mTORC1. Thus, mTORC1 links HIF-1\u03b1-driven vasculogenesis with the FGF-10\/FGFR2b\/Spry2 airway branching periodicity regulator.<\/jats:p>","DOI":"10.1152\/ajplung.00348.2009","type":"journal-article","created":{"date-parts":[[2010,7,12]],"date-time":"2010-07-12T10:20:35Z","timestamp":1278930035000},"page":"L455-L471","source":"Crossref","is-referenced-by-count":29,"title":["Control of HIF-1\u03b1 and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10\/FGFR2b\/Spry2 airway branching periodicity clock"],"prefix":"10.1152","volume":"299","author":[{"given":"C. L.","family":"Scott","sequence":"first","affiliation":[{"name":"Centre for Cardiovascular and Lung Biology, Division of Medical Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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