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VEGF Induces Tie2 Shedding via a Phosphoinositide 3-Kinase/Akt–Dependent Pathway to Modulate Tie2 Signaling
- Source :
- Arteriosclerosis, Thrombosis, and Vascular Biology. 27:2619-2626
- Publication Year :
- 2007
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2007.
-
Abstract
- Objective— Tie2 and its ligands, the angiopoietins (Ang), are required for embryonic and postnatal angiogenesis. Previous studies have demonstrated that Tie2 is proteolytically cleaved, resulting in the production of a 75-kDa soluble receptor fragment (sTie2). We investigated mechanisms responsible for Tie2 shedding and its effects on Tie2 signaling and endothelial cellular responses. Methods and Results— sTie2 bound both Ang1 and Ang2 and inhibited angiopoietin-mediated Tie2 phosphorylation and antiapoptosis. In human umbilical vein endothelial cells, Tie2 shedding was both constitutive and induced by treatment with PMA or vascular endothelial growth factor (VEGF). Constitutive and VEGF-inducible Tie2 shedding were mediated by PI3K/Akt and p38 MAPK. Tie2 shedding was blocked by pharmacological inhibitors of either PI3K or Akt as well as by overexpression of the lipid phosphatase PTEN. In contrast, sTie2 shedding was enhanced by overexpression of either dominant negative PTEN, which increased Akt phosphorylation, or constitutively active, myristoylated Akt. Conclusions— These findings demonstrate that VEGF regulates angiopoietin-Tie2 signaling by inducing proteolytic cleavage and shedding of Tie2 via a novel PI3K/Akt-dependent pathway. These results suggest a previously unrecognized mechanism by which VEGF may inhibit vascular stabilization to promote angiogenesis and vascular remodeling.
- Subjects :
- Vascular Endothelial Growth Factor A
Pyridines
Angiogenesis
Apoptosis
p38 Mitogen-Activated Protein Kinases
Mice
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
Phosphorylation
Cells, Cultured
Phosphoinositide-3 Kinase Inhibitors
biology
Kinase
Imidazoles
Dipeptides
Receptor, TIE-2
Cell biology
Vascular endothelial growth factor
embryonic structures
cardiovascular system
Tetradecanoylphorbol Acetate
Cardiology and Cardiovascular Medicine
Signal Transduction
medicine.medical_specialty
Morpholines
Neovascularization, Physiologic
Matrix Metalloproteinase Inhibitors
Transfection
Angiopoietin-2
Internal medicine
Angiopoietin-1
medicine
Animals
Humans
PTEN
Protein Kinase Inhibitors
Protein kinase B
PI3K/AKT/mTOR pathway
Phosphoinositide 3-kinase
PTEN Phosphohydrolase
Endothelial Cells
Fibroblasts
Matrix Metalloproteinases
Peptide Fragments
Endocrinology
chemistry
Chromones
NIH 3T3 Cells
biology.protein
Proto-Oncogene Proteins c-akt
Peptide Hydrolases
Subjects
Details
- ISSN :
- 15244636 and 10795642
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Accession number :
- edsair.doi.dedup.....88d89d3ea98f9d713de733d92746f40c