AIMS: Development of the respiratory tree requires co-ordinated signalling between airway and vascular tissues but the link between these processes remains unclear. The mammalian target of rapamycin complex-1 (mTORC1) can amplify hypoxia inducible factor-1a (HIF- 1a)-mediated vasculogenesis by interacting with an N-terminal mTOR binding (TOS) motif. We hypothesised that mTORC1 regulation by the fibroblast growth factor (FGF)- 10/FGF-receptor2b/Sprouty2 airway branching periodicity regulator links vasculogenic HIF- 1a activity to airway growth. METHODS: Bicameral cultures of human bronchial epithelial cells (16HBE14o- or "HBE") and human embryonic lung fibroblasts (HELF) were maintained at fetal or alveolar PO₂ to study the induction of vasculogenic signalling by FGF-10 and regulators of mTORC1. Results were compared to the pattern of vasculogenesis in gestation day 12.5 wild-type and TSC1^-/- mice. RESULTS: mTORC1 activation in HBE at fetal PO₂ evoked a 5-fold, rapamycin- sensitive, amplification of HIF-1a above endogenous levels and induced vascular endothelial growth factor (VEGF) release and vascular differentiation (Flk1, sprouting) in HELF co-cultures. This was abolished by null- mutation of the HIF-1a-mTORC1 docking motif. mTORC1 activity in vivo occurred in pseudoglandular epithelial lung buds and hyper- activation in E12.5 murine TSC1^-/- fetuses raised VEGF expression and disaggregated Tie2-positive vascular bundles. This intrinsic mTORC1 activity was responsive to airway branching regulators as, in HBE, FGF-10 induced a concentration-dependent activation/repression of rapamycin-sensitive HIF-1a. Sprouty2 over-expression abolished HIF-1a activity induced by either FGF-10 or Rheb, the upstream activating G-protein of mTORC1. CONCLUSION: We postulate a model of co-ordinated airway and vascular branching morphogenesis whereby mTORC1 integrates HIF-1a-driven vasculogenesis with the FGF-10/FGFR2b/Sprouty2 airway branching periodicity regulator.