Abstract
Angiogenesis and vascular cell proliferation are pivotal in physiological and pathological processes including atherogenesis, restenosis, wound healing, and cancer development. Here we show that mammalian target of rapamycin (mTOR) signaling plays a key role in hypoxia-triggered smooth muscle and endothelial proliferation and angiogenesis in vitro. Hypoxia significantly increased DNA synthesis and proliferative responses to platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) in rat and human smooth muscle and endothelial cells. In an in vitro 3-dimensional model of angiogenesis, hypoxia increased PDGF- and FGF-stimulated sprout formation from rat and mouse aortas. Hypoxia did not modulate PDGF receptor mRNA, protein, or phosphorylation. PI3K activity was essential for cell proliferation under normoxic and hypoxic conditions. Activities of PI3K-downstream target PKB under hypoxia and normoxia were comparable. However, mTOR inhibition by rapamycin specifically abrogated hypoxia-mediated amplification of proliferation and angiogenesis, but was without effect on proliferation under normoxia. Accordingly, hypoxia-mediated amplification of proliferation was further augmented in mTOR-overexpressing endothelial cells. Thus, signaling via mTOR may represent a novel mechanism whereby hypoxia augments mitogen-stimulated vascular cell proliferation and angiogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Animals
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Cell Division / drug effects
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Cell Hypoxia / physiology*
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Cells, Cultured
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Chromones / pharmacology
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DNA / biosynthesis
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DNA / drug effects
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Dose-Response Relationship, Drug
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Fibroblast Growth Factor 2 / pharmacology
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Mice
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Models, Biological
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Morpholines / pharmacology
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Muscle, Smooth, Vascular / blood supply*
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects
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Neovascularization, Physiologic / drug effects
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Neovascularization, Physiologic / physiology*
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Phosphatidylinositol 3-Kinases / drug effects
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Platelet-Derived Growth Factor / pharmacology
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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RNA, Messenger / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Receptors, Platelet-Derived Growth Factor / drug effects
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Receptors, Platelet-Derived Growth Factor / genetics
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Receptors, Platelet-Derived Growth Factor / metabolism
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases
Substances
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Chromones
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Morpholines
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins
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RNA, Messenger
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Fibroblast Growth Factor 2
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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DNA
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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mTOR protein, rat
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Receptors, Platelet-Derived Growth Factor
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Sirolimus