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Control of HIF-1{alpha} and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock.
- Source :
-
American journal of physiology. Lung cellular and molecular physiology [Am J Physiol Lung Cell Mol Physiol] 2010 Oct; Vol. 299 (4), pp. L455-71. Date of Electronic Publication: 2010 Jul 09. - Publication Year :
- 2010
-
Abstract
- Lung development requires coordinated signaling between airway and vascular growth, but the link between these processes remains unclear. Mammalian target of rapamycin complex-1 (mTORC1) can amplify hypoxia-inducible factor-1α (HIF-1α) vasculogenic activity through an NH(2)-terminal mTOR binding (TOS) motif. 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-1α TOS motif participated in epithelial-mesenchymal vascular signaling. mTORC1 activation by insulin significantly amplified HIF-1α activity at fetal Po(2) (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-1α by mTORC1 was abolished on expression of a HIF-1α (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(-/-) 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(2), FGF-10 induced mTORC1 and amplified HIF-1α 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-1α-driven vasculogenesis with the FGF-10/FGFR2b/Spry2 airway branching periodicity regulator.
- Subjects :
- Animals
Blotting, Western
Bronchi cytology
Bronchi metabolism
Cells, Cultured
Circadian Rhythm
Embryo, Mammalian cytology
Embryo, Mammalian metabolism
Enzyme-Linked Immunosorbent Assay
Epithelial Cells metabolism
Fetus cytology
Fetus metabolism
Fibroblast Growth Factor 10 genetics
Fibroblasts cytology
Fibroblasts metabolism
Humans
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Immunoenzyme Techniques
Immunoprecipitation
Lung cytology
Mesoderm cytology
Mesoderm metabolism
Mice
Nerve Tissue Proteins genetics
RNA, Messenger genetics
Rats
Rats, Sprague-Dawley
Receptor, Fibroblast Growth Factor, Type 2 genetics
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors genetics
Tuberous Sclerosis Complex 1 Protein
Tumor Suppressor Proteins physiology
Biological Clocks
Fibroblast Growth Factor 10 metabolism
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Lung metabolism
Neovascularization, Physiologic
Nerve Tissue Proteins metabolism
Receptor, Fibroblast Growth Factor, Type 2 metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1504
- Volume :
- 299
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Lung cellular and molecular physiology
- Publication Type :
- Academic Journal
- Accession number :
- 20622121
- Full Text :
- https://doi.org/10.1152/ajplung.00348.2009