PTEN modulates vascular endothelial growth factor-mediated signaling and angiogenic effects.
Phosphatidylinositol 3-kinase is activated by vascular endothelial growth factor (VEGF), and many of the angiogenic cellular responses of VEGF are regulated by the lipid products of phosphatidylinositol 3-kinase. The tumor suppressor PTEN has been shown to down-regulate phosphatidylinositol 3-kinase signaling, yet the effects of PTEN on VEGF-mediated signaling and angiogenesis are unknown. Inhibition of endogenous PTEN in cultured endothelial cells by adenovirus-mediated overexpression of a dominant negative PTEN mutant (PTEN-C/S) enhanced VEGF-mediated Akt phosphorylation, and this effect correlated with decreases in caspase-3 cleavage, caspase-3 activity, and DNA degradation after induction of apoptosis with tumor necrosis factor-alpha. Overexpression of PTEN-C/S also enhanced VEGF-mediated endothelial cell proliferation and migration. In contrast, overexpression of wild-type PTEN inhibited the anti-apoptotic, proliferative, and chemotactic effects of VEGF. Moreover, PTEN-C/S increased the length of vascular sprouts in the rat aortic ring assay and modulated VEGF-mediated tube formation in an in vitro angiogenesis assay, whereas PTEN-wild type inhibited these effects. Taken together, these findings demonstrate that PTEN potently modulates VEGF-mediated signaling and function and that PTEN is a viable target in therapeutic approaches to promote or inhibit angiogenesis.
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- Vascular Endothelial Growth Factors
- Vascular Endothelial Growth Factor A
- Tumor Suppressor Proteins
- Signal Transduction
- Rats, Sprague-Dawley
- Rats
- Phosphoric Monoester Hydrolases
- Phosphatidylinositol 3-Kinases
- PTEN Phosphohydrolase
- Neovascularization, Physiologic
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Vascular Endothelial Growth Factors
- Vascular Endothelial Growth Factor A
- Tumor Suppressor Proteins
- Signal Transduction
- Rats, Sprague-Dawley
- Rats
- Phosphoric Monoester Hydrolases
- Phosphatidylinositol 3-Kinases
- PTEN Phosphohydrolase
- Neovascularization, Physiologic