Journal article
Hypoxia-Induced Endothelial Proliferation Requires Both mTORC1 and mTORC2
Circulation research, Vol.100(1), pp.79-87
01/05/2007
Handle:
https://hdl.handle.net/2376/112279
PMID: 17110594
Abstract
A central regulator of cell growth that has been implicated in responses to stress such as hypoxia is mTOR (mammalian Target Of Rapamycin). We have shown previously that mTOR is required for angiogenesis in vitro and endothelial cell proliferation in response to hypoxia. Here we have investigated mTOR-associated signaling components under hypoxia and their effects on cell proliferation in rat aortic endothelial cells (RAECs). Hypoxia (1% O2) rapidly (>30 minutes) and in a concentration-dependent manner promoted rapamycin-sensitive and sustained phosphorylation of mTOR-Ser2448 followed by nuclear translocation in RAECs. Similarly, hypoxia induced phosphorylation of the mTORC2 substrate Akt-Ser473 (3 to 6 hours at 1% O2) and a brief phosphorylation peak of the mTORC1 substrate S6 kinase–Thr389 (10 to 60 minutes). Phosphorylation of Akt was inhibited by mTOR knockdown and partially with rapamycin. mTOR knockdown, rapamycin, or Akt inhibition specifically and significantly inhibited proliferation of serum-starved RAECs under hypoxia (P<0.05; n≥4). Similarly, hypoxia induced Akt-dependent and rapamycin-sensitive proliferation in mouse embryonic fibroblasts. This response was partially blunted by hypoxia-inducible factor-1α knockdown and not affected by TSC2 knockout. Finally, mTORC2 inhibition by rictor silencing, especially (P<0.001; n=7), and mTORC1 inhibition by raptor silencing, partially (P<0.05; n=7), inhibited hypoxia-induced RAEC proliferation. Thus, mTOR mediates an early response to hypoxia via mTORC1 followed by mTORC2, promoting endothelial proliferation mainly via Akt signaling. mTORC1 and especially mTORC2 might therefore play important roles in diseases associated with hypoxia and altered angiogenesis.
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Details
- Title
- Hypoxia-Induced Endothelial Proliferation Requires Both mTORC1 and mTORC2
- Creators
- Weimin Li - From the Departments of Research (W.L., M.P., E.J.B., R.J.) and Internal Medicine (E.J.B.), University of Basel; and Department of Biochemistry (K.D.M., M.N.H.), Biocenter, University of Basel, Switzerland. Current address for W.L.: National Cancer Institute, Mouse Cancer Genetic Program, Frederick, MdMarco PetrimpolKlaus MolleMichael HallEdouard BattegayRok Humar
- Publication Details
- Circulation research, Vol.100(1), pp.79-87
- Academic Unit
- Biomedical Sciences, Department of
- Publisher
- American Heart Association, Inc
- Identifiers
- 99900547725801842
- Language
- English
- Resource Type
- Journal article